Received: 12 August 2018 | Accepted: 22 August 2018

DOI: 10.1002/jcp.27411

REVIEW ARTICLE

Cyclooxygenase‐2 in cancer: A review

Nasser Hashemi Goradel1 | Masoud Najafi2 | Eniseh Salehi3 | Bagher Farhood4 |

Keywan Mortezaee5

1
Department of Medical Biotechnology,
School of Advanced Technologies in Medicine, Abstract
Tehran University of Medical Sciences, Cyclooxygenase‐2 (COX‐2) is frequently expressed in many types of cancers exerting
Tehran, Iran
2 a pleiotropic and multifaceted role in genesis or promotion of carcinogenesis and
Radiology and Nuclear Medicine Department,
School of Paramedical Sciences, Kermanshah cancer cell resistance to chemo‐ and radiotherapy. COX‐2 is released by cancer‐
University of Medical Sciences,
associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and cancer cells to the
Kermanshah, Iran
3
Department of Anatomy, School of Medicine, tumor microenvironment (TME). COX‐2 induces cancer stem cell (CSC)‐like activity,
Tehran University of Medical Sciences, and promotes apoptotic resistance, proliferation, angiogenesis, inflammation, inva-
Tehran, Iran
4
sion, and metastasis of cancer cells. COX‐2 mediated hypoxia within the TME along
Departments of Medical Physics and
Radiology, Faculty of Paramedical Sciences, with its positive interactions with YAP1 and antiapoptotic mediators are all in favor
Kashan University of Medical Sciences,
of cancer cell resistance to chemotherapeutic drugs. COX‐2 exerts most of the
Kashan, Iran
5
Department of Anatomy, School of Medicine,
functions through its metabolite prostaglandin E2. In some and limited situations,
Kurdistan University of Medical Sciences, COX‐2 may act as an antitumor enzyme. Multiple signals are contributed to the
Sanandaj, Iran
functions of COX‐2 on cancer cells or its regulation. Members of mitogen‐activated
Correspondence protein kinase (MAPK) family, epidermal growth factor receptor (EGFR), and nuclear
Keywan Mortezaee, Department of Anatomy,
School of Medicine, Kurdistan University of
factor‐κβ are main upstream modulators for COX‐2 in cancer cells. COX‐2 also has
Medical Sciences, Sanandaj 6681853363, Iran. interactions with a number of hormones within the body. Inhibition of COX‐2
Email: keywan987@yahoo.com;
mortezaee.k@muk.ac.ir
provides a high possibility to exert therapeutic outcomes in cancer. Administration of
COX‐2 inhibitors in a preoperative setting could reduce the risk of metastasis in
cancer patients. COX‐2 inhibition also sensitizes cancer cells to treatments like radio‐
and chemotherapy. Chemotherapeutic agents adversely induce COX‐2 activity.
Therefore, choosing an appropriate chemotherapy drugs along with adjustment of the
type and does for COX‐2 inhibitors based on the type of cancer would be an effective
adjuvant strategy for targeting cancer.

KEYWORDS
cancer cell, COX‐2, NF‐κβ, prostaglandin

1 | INTRODUCTION inflammation (H.‐Y. Qiu et al., 2016). COX‐2 is a prostaglandin

Cyclooxygenases (COXs) have three isoforms: COX‐1, COX‐2, and
COX‐3 (B. Li, Lu, et al., 2017; Wong et al., 2017). COX‐2 is a
membrane‐bound (W. Xu, Huang, et al., 2018), short‐living (Obermoser
et al., 2018), and rate‐limiting enzyme (W. Xu, Huang, et al., 2018)
discovered in 1991 (Goswami & Sharma‐Walia, 2016) and has long
been known as a target for relief of pain and treatment of
(PG)–endoperoxide synthase 2 (X. Xu, Huang, et al., 2018) enzyme
responsible for generation of prostanoids like prostaglandin E2 (PGE2)
that are contributed to the modulation of multiple procarcinogenic
effects (Dannenberg, Lippman, Mann, Subbaramaiah, & DuBois, 2005;
F. Li & Zhu, 2015). COX‐2 expression is negligible in normal cells
(Gurram et al., 2018) in which its basal expression only occurs within
stomach (Su, Zhang, & Zhu, 2016), kidney, central nervous system, and

J Cell Physiol. 2018;1-17. wileyonlinelibrary.com/journal/jcp © 2018 Wiley Periodicals, Inc. | 1

2 |
in organs of female reproduction (Obermoser et al., 2018). However, it
is expressed frequently at the tumorigenic nests in most types of
cancers (Gurram et al., 2018; Raj et al., 2018), including adenocarci-
noma, squamous cell carcinoma (SCC), cholangiocarcinoma, transi-
tional cell carcinoma, endometrial carcinoma (Dannenberg et al.,
2005), and hepatocellular carcinoma (HCC; Mortezaee, 2018). In fact,
the tumor microenvironment (TME) is an inducer for COX‐2 over-
expression (Ohtsuka et al., 2018). This overexpression is due to
dysregulated control over its transcriptional or post‐transcriptional
levels (Y. Liu, Borchert, Surazynski, & Phang, 2008), so it could be a
promising marker for identification of the tumor from normal cells
(Gurram et al., 2018; Yue, Nguyen, Zellmer, Zhang, & Zorlutuna, 2018).
COX‐2 is also a constituent of the tumor‐derived exosomes
(Theodoraki, Hoffmann, & Whiteside, 2018). Oncogenic viruses
(Charalambous, Maihöfner, Bhambra, Lightfoot, & Gooderham,
2003), cancer promotors (Y. Xu, Yang, et al., 2018), radiation (Kirk
et al., 2018), and chemotherapy (Ikeya, Sakabe, Yamada, Naito, &
Tokura, 2018) and proinflammatory cytokines (H.‐Y. Qiu et al., 2016)
are inducers of COX‐2 expression in cancer cells. COX‐2 over-
expression promotes carcinogenesis (Hung et al., 2004), increases the
rate of cancer recurrence (Montezuma et al., 2018) and reduces
survival (Höing et al., 2018; Sharma et al., 2005; H. Sun et al., 2017) in
affected patients, and it is related to cancer cell resistance to chemo‐
and radiotherapy (J. Li, Zhou, et al., 2017).
COX‐2 via its pleiotropic effects could evolve a wide range of
activities (Noda et al., 2002). Expression of this rapid response gene
(Y. Hao et al., 2017) occurs as probably an early event (Charalambous
et al., 2003) promoting cancer cell survival, growth, and angiogenesis
(Noda et al., 2002), and that COX‐2 transgene has been recognized to
be a sufficient initiator of cancers like HCC (H. Chen et al., 2017).
There is also evidence for the involvement of COX‐2 in cancer
development (Dong et al., 2018) and invasion (Greenhough et al.,
2009), and its contribution to tumor aggressiveness and poor patient
prognosis (Esbona et al., 2018).
The COX‐2 blockade has been shown to provide chemopre-
ventive for a number of cancers (Harris, Beebe‐Donk, & Alshafie,
2007), so targeting this enzyme might be a promising approach
for cancer therapy. To write this review, we intended to
summarize roles for COX‐2 in cancer focusing on its upstream
or downstream signaling cascades and targeting for cancer
therapeutic approaches. PubMed database was searched for
recent and novel articles in this context. The criteria for article
selection was based on the novelty, time of publication, quality of
the journals, and number of citations. A total number of 1,100
papers were scanned for this review with the keywords “COX‐2”
and “cancer.”
2 | COX ‐2 S TRUCTURE, A CTIVATION,
AN D D EGRA DATION
COX‐2 gene is located on the chromosome 1q25.2‐q25.3 in human
subjects (W. Xu, Huang, et al., 2018). Degradation of COX‐2 occurs in
HASHEMI ET AL.
the proteasome in association with endoplasmic reticulum (ER;
Sample, Zhao, Qiang, & He, 2017). Due to existence of many
polymorphisms in the COX‐2 gene, susceptibility among individuals
to cancer is different (W. Xu, Huang, et al., 2018). Proteins
specifically binding to the COX‐2 promotor would take an important
role in promotion of tumorigenesis (Xuan et al., 2016). COX‐2
promoter contains a 3‐untranslated region (3‐UTR) that could be a
target for microRNAs (miRNAs) like miR‐144 for suppression of
cancer progression (Yao, Gu, Wang, & Xue, 2018). There are AU‐rich
elements (AREs) in the 3‐UTR of COX‐2. These AREs could influence
messenger RNA (mRNA) decay and protein translation (Dannenberg
et al., 2005) probably through interaction with Hu antigen‐R (HuR;
Janakiraman et al., 2017). Stability in the COX‐2 mRNA is regulated
by p38 mitogen‐activated protein kinase (MAPK; Hung et al., 2004)
and K‐ras (Araki et al., 2003).
Promoter of COX‐2 brings sites (response elements) for the
followings:
• Two sites for nuclear factor‐κβ (NF‐κβ; Charalambous et al., 2003)
by which this nuclear factor can influence COX‐2 gene transcription
(X. Zheng et al., 2018). P300 and NF‐κβ work as co‐ and
transactivator for COX‐2 promoter, respectively (Mortezaee,
2018). Recruitment of p300 to the COX‐2 promoter is mediated
by tonicity‐responsive enhancer binding protein (J.H. Lee et al.,
2018), while suppression of nuclear localization for this coactivator
is mediated by N‐myc (and STAT) interactor (NMI; J. Wang, Zou,
et al., 2017). Factors like thyroid hormone receptor interactor 4
(TRIP4) have synergy with p300 for inducing COX‐2 promoter
directly (J. Hao et al., 2018). Oxidative stress is an inducer of the
inflammatory enhanceosome sites on the COX‐2 promoter (J.H. Lee
et al., 2018).
• Sites for several cytokines like interleukin (IL)‐6 (J. Wang, Zou,
et al., 2017).
• A site for cyclic AMP response element (CRE). CRE is a target for
protein binding (CREB) via activation by p38 MAPK, so this site is
for transcriptional activation of COX‐2 (Yadav et al., 2018). CRE is
also a binding site for c‐Jun (Qin et al., 2015).
• A site for TCF‐4‐binding element through which activation of COX‐
2 promoter is mediated by β‐catenin (Araki et al., 2003).
• TEAD binding sites for interaction with factors like YAP
contributed to the regulation of COX‐2 transcription favoring
drug resistance in cancer cells (W. Li, Cao, et al., 2017).
• Activator protein‐2 (AP‐2) and specificity protein binding sites
are responsive to lipopolysaccharide (Wong et al., 2017). AP‐2
is a transactivator for COX‐2 (X. Wang, Yu, et al., 2017;
Figure 1).
3 | P Gs AR E I M P O RTA NT TAR GE T S F O R
COX ‐2 I N TH E P RO M O TIO N O F CA NC ER
It is accepted that COX‐2 contribution to carcinogenesis is mediated
through overproduction of PGs. Metabolites of these PGs released
HASHEMI ET AL.
F I G U R E 1 Cyclooxygenase‐2 (COX‐2) promoter. AP‐2: activator protein‐2; ARE: AU‐rich elements; CRE: cyclic AMP response
element; CREB: CRE protein binding; HuR: Hu Antigen‐R; IL: interleukin; mRNA: messenger RNA; NF‐κβ: nuclear factor‐κβ; 3‐UTR,
3‐untranslated region; TBE: Tcf‐4‐binding element; TEAD: TEA domain
into the urine are now considered as approved biomarkers for
prediction of cancer risk (Cui et al., 2017). PGE2 is a cardinal
mediator of inflammation playing a key role in carcinogenesis (Cui
et al., 2017). There is a positive‐feedback loop between COX‐2
expression and PGE2 (D. Wang, Buchanan, Wang, Dey, & DuBois,
2005). The effects of PGE2 are exerted through interaction with its
putative transmembrane G‐protein‐coupled EP receptors (EP1–EP4),
especially EP1 and EP4 (Majumder et al., 2018; Majumder, Landman,
Liu, Hess, & Lala, 2015; Pan et al., 2016). PGE2 is responsible for
induction of COX‐2 expression through activation of ROS/AKT/
activator protein‐1 (E.‐H. Kim et al., 2008), Ras (D. Wang et al., 2005),
and Ras subfamily RhoC (Lang et al., 2017).
COX‐2 action on PGs especially PGE2 accounts for diverse
functions in favor of tumor promotion as follows:
(1) Apoptosis resistance via upregulation of Bcl‐2 (Hosseini et al.,
2018; Todoric, Antonucci, & Karin, 2016).
(2) Angiogenesis through upregulation of vascular endothelial
growth factor (VEGF; Hosseini et al., 2018; Todoric et al., 2016).
(3) Metastasis by upregulation of matrix metalloproteinases (MMPs)
type 2 and 9 (Hosseini et al., 2018; Todoric et al., 2016) and IL‐11
(Singh, Berry, Shoher, & Lucci, 2006) along with activation of
oncogenic miR526b (Majumder et al., 2015).
(4) Tumor growth via upregulation of epidermal growth factor
receptor (EGFR; Hosseini et al., 2018; Todoric et al., 2016).
(5) Maintenance of cancer stem cell (CSC)‐like activity via activation
of WNT/β‐catenin/TCF (Greenhough et al., 2009) and miR526b
(Majumder et al., 2015), and suppression of dual specificity
phosphatase 2 (Hou et al., 2017).
(6) Cancer cell survival (Majumder et al., 2018) and inflammation
(Ramu et al., 2018) through interaction with PI3K/AKT.
(7) Cancer cell invasion via upregulation of extracellular signal‐
regulated kinase (ERK; Majumder et al., 2018) and membrane
proteases (C. Ko et al., 2017).
(8) Modulation of the immune system through increase of the
activity for regulatory T cells (Tregs; Sharma et al., 2005; via
induction of Nr4a expression; Hibino et al., 2018) and the activity
for protumor M2 cells (Esbona et al., 2018; Figure 2).
| 3
4 | CO NTRIBUTION OF
COX ‐2‐ EX P R ES S I N G T U M O R‐A S S O C IA T E D
MACROPHAGES (TAMs) TO T UMOR
PROGRESSION
TAMs are part of inflammatory circuits that exhibit antitumor (M1) or
protumor (M2) features depending on the cytokine concentration in the
tumor milieu. COX‐2 is not a specific determinator of macrophage
polarity toward either type. In human and animal intestinal adenomas, it
has been attested no conspicuous phonotypic alterations in macrophages
expressing COX‐2 (Hull et al., 2017). Although it has been asserted that
COX‐2 inhibition could make a switch in the TAM phenotype from M2 to
M1 (Nakanishi et al., 2011), this is not persuasive to come to the
conclusion of COX‐2 acting as TAM switcher toward M2 cells. A point in
this context is that M1 is a proinflammatory phenotype, while M2 is an
anti‐inflammatory cell type (Xiang et al., 2018). Another point is that
polarity toward M1 cell type is stimulated by NF‐κβ that influences
inflammatory states in macrophages in an active heterodimer form (p50‐
p65; Genard et al., 2018). As it has been discussed, NF‐κβ is a
transactivator for COX‐2 promoter contributed to activation of COX‐2
in both cancer cells (Charalambous et al., 2003) and TAMs (Hung et al.,
2004). There is also evidence for protumoral activity of COX‐2 in
macrophages (Lu Gan et al., 2016). Taken together, it could be speculated
that macrophage polarity is not influenced by COX‐2. Rather, COX‐2
could act as a promoter of macrophage protumoral activity.
Upon irradiation, infiltration of the COX‐2 expressing TAMs to the
tumor milieu occurs. This infiltration promotes tumor growth (Esbona
et al., 2018), reduces patient survival (Esbona et al., 2018), and
influences normal epithelial cells around the tumor by relaying
protumorigenic signals (S.C. Ko et al., 2002). In addition, release of
COX‐2 from M2 cells is also contributed to tumor invasion (Tjiu et al.,
2009), angiogenesis (Rong et al., 2016), and metastasis (Lu Gan et al.,
2016). COX‐2 expression in M2 cells induces protein kinase B (AKT)
pathway in cancer cells for secretion of MMPs (mediators of invasion
and metastasis; Lu Gan et al., 2016; Tjiu et al., 2009). M2 macrophages
are also able to induce EP1 expression in cancer cells for the
promotion of angiogenesis (Rong et al., 2016). In addition, TAMs
express sphingosine kinase‐1 (SphK1)/sphingosine 1‐phosphate (S1P;
4 | HASHEMI ET AL.

F I G U R E 2 Cyclooxygenase‐2 (COX‐2) acting as a procancer enzyme. AKT: protein kinase B; APAF: apoptosis protease‐activating factor;
CSC: cancer stem cell; CYP19: aromatase cytochrome P450; DGLA: dihomo‐γ‐linolenic acid; EGFR: epidermal growth factor receptor; EMT:
epithelial–mesenchymal transition; ERK1: extracellular signal‐regulated kinase‐1; HIF: hypoxia inducible factor; IDO1: indoleamine 2,3‐
dioxygenase 1; LKB1: liver kinase B1; MAPK: mitogen‐activated protein kinase; MMP: matrix metalloproteinases; mTOR: mechanistic target of
rapamycin; NF‐κβ: nuclear factor‐κβ; PG: prostaglandin; PI3K: phosphoinositide 3‐kinase; PKC: protein kinase C; PTEN: phosphatase and tensin
homologue; RLS: reactive lipid species; STAT3: signal transducer and activator of transcription‐3; TCF: T‐cell factor; TGF‐α: tumour growth
factor‐α; TGF‐β: tumour growth factor‐β; VEGF: vascular endothelial growth factor

F I G U R E 3 Interaction between cyclooxygenase‐2 (COX‐2) derived from cancer cells with cells in the tumor microenvironment.
5‐MTP: 5‐methoxytryptophan; ADAM17: A disintegrin and metalloproteinase 17; CAF: cancer‐associated fibroblast; CTL: cytotoxic T
lymphocyte; IFN: interferon; NF‐κβ: nuclear factor‐κβ; PGE2: prostaglandin E2; TEC: tumor endothelial cell; Sp1: specificity protein;
SASP: senescence‐associated secretory phenotype; Treg: regulatory T cell
HASHEMI ET AL. | 5

F I G U R E 4 Signaling pathways or factors contributed to positive or negative regulation of cyclooxygenase‐2 (COX‐2) in cancer cells. AhR:
arylhydrocarbon receptor; AKT: protein kinase B; AMPK: AMP‐activated protein kinase; ANXA5: annexin A; ARNT: aryl hydrocarbon receptor
nuclear translocator; CREB: cyclic AMP response element protein binding; DUSP2: dual specificity phosphatase 2; EGFR: epidermal growth
factor receptor; ER: endoplasmic reticulum; ERK: extracellular signal‐regulated kinase; GATA-4: GATA-binding protein 4; HGF: hepatocyte
growth factor; HIF: hypoxia inducible factor; IL: interleukin; JNK: c‐Jun NH2‐terminal kinase; LKB1: liver kinase B1; m: mutant; MGL:
monoglyceride lipase; NF‐κβ: nuclear factor‐κβ; NMI: N‐myc (and STAT) interactor; PI3K: phosphoinositide 3‐kinase; PKC: protein kinase C;
POX: proline oxidase; PTEN: phosphatase and tensin homologue; ROS: reactive oxygen species; SIRT: sirtuin; Sp1: specificity protein; TRIP4:
thyroid hormone receptor interactor 4; TNF‐α: tumour necrosis factor‐α; UV: ultraviolet; VRCZ: voriconazole; wt: wild type

Furuya et al., 2017) and a disintegrin and metalloproteinase 17 mediated by COX‐2 would remove a possible barrier made by normal
(ADAM17; Bohrer et al., 2016) that are known for their role in fibroblasts against tumor progression. For example, normal fibro-
regulation of COX‐2 expression in cancer cells (Figure 3). blasts release factors like 5‐methoxytryptophan acting as inhibitors
for COX‐2 expression in cancer cells (Cheng et al., 2016; Figure 3).

5 | CONT RIBUTIO N OF
COX ‐2 ‐E X P R E S S I N G C A N C E R ‐A S S O C I A T E D
FIBROBLAST S (CAFs) TO TUMORIGE NESIS
There is a positive relation between COX‐2 and collagen synthesis in
tumor cells attested by either pharmacologic inhibition of COX‐2
(Esbona et al., 2016; Krishnamachary et al., 2017) or using proline
oxidases (Y. Liu et al., 2008), and that this relation is considered to be
a driving force for reducing the time of cancer metastasis (Esbona
et al., 2018). CAFs are responsible for production of the high amount
of collagen in cancer cells (Krishnamachary et al., 2017). There is a
positive relation between COX‐2 expression with the number of
CAFs (Krishnamachary et al., 2017). CAFs are major producers of
COX‐2 to the TME (Su et al., 2016). COX‐2 release by cancer cells to
this milieu could also influence CAFs into attaining a senescence‐
associated secretory phenotype (SASP) called senescence CAFs that
are inducers of cancer cell motility (Kabir et al., 2016). Therefore,
COX‐2 provides a link between cancer cells with CAFs for the
promotion of cancer, and that increasing in the number of CAFs
6 | CO X‐ 2 A ND A UTO P HA GY I N CAN CER
Autophagy is a process of waste disposal for degradation of damaged
organelles/proteins. A dysfunction (dysregulation) in this process is
contributed to tumorigenesis (Mortezaee, 2018). Autophagy‐related
(ATG) gene ATG6 activates COX‐2 in a CREB‐depended mechanism
(Qiang et al., 2017). COX‐2 is also regulated by p62 (Sample et al.,
2017). P62 is an intracellular ubiquitin‐binding protein responsible
for the generation of autophagosome after interaction with LC3
(Mortezaee, 2018; Figure 4).
7 | CO X‐ 2 A ND O X I D AT IV E S TR ES S
IN CA NC ER
Reactive oxygen species (ROS) are among COX‐2 derived paracrine
mediators for inducing mutation in cells (S.C. Ko et al., 2002).
COX‐2 is involved in peroxidation of lipids (Y. Xu, Yang, et al., 2018)
6 |
taking a role for the generation of reactive lipid species (RLS; Wagner,
Mullally, & Fitzpatrick, 2006). Cyclopentenone PGs are an example for
these COX‐2‐derived RLS (Higdon, Diers, Oh, Landar, & Darley‐Usmar,
2012; Wagner et al., 2006) contributed to inhibition of the tumor‐
suppressing liver kinase B1 (LKB1; Wagner et al., 2006). ROS have two
diverse effects on COX‐2 in cancer cells by being either inducer (E.‐H.
Kim et al., 2008) or inhibitor (Jeong, Kim, Lee, & Kim, 2017; Y. Liu et al.,
2008) of this enzyme. Induction of COX‐2 by ROS is mediated by
activation of AKT (at Ser473), EGFR (at Tyr1068; J. Lee et al., 2017) and
ERK (J. Qiu, Shi, & Jiang, 2017), and inhibition of COX‐2 is mediated by
the stimulatory effect of ROS on AMP‐activated protein kinase
(AMPK; Jeong et al., 2017). The ROS/ERK/COX‐2 is contributed to
cancer cell migration and invasion (J. Qiu et al., 2017; Figure 4).
CSCs and bulk cancer cells are vulnerable to alterations in the
intracellular redox state (C. Lu, Laws, Eskandari, & Suntharalingam,
2017) depended on the ROS concentration. Low ROS concentration
promotes cell proliferation via compensatory increase of the activity for
antioxidative enzymes, while high ROS concentration induces mito-
chondrial pathway of apoptosis through inducing release of proapopto-
tic proteins from mitochondria into cytosol (Mortezaee, 2018).
8 | COX ‐2 I S A MEDIATOR OF
I N F L A M M A T IO N I N C A N C E R
Inflammation is an inducer of carcinogenesis in which an inflamma-
tory microenvironment is considered as a promoter of cancer
development and invasiveness (Echizen, Oshima, Nakayama, &
Oshima, 2018). COX‐2 is a proinflammatory enzyme (Pollock et al.,
2018) overexpressed at the inflammatory site of cancer (Raj et al.,
2018). There is a reciprocal positive feedback between COX‐2 and
inflammatory mediators with either one inducing another (Desai,
Prickril, & Rasooly, 2018; Hosseini et al., 2018; Figure 4).
9 | COX ‐2 AN D T U M O R IM M U N I T Y
COX‐2 is able to instruct an immune phenotype through inducing
immune cell recruitment into the tumor tissue to induce an
immunosuppressive state in the tumor milieu (Lang et al., 2006) in
favor of cancer cell activation (Höing et al., 2018). COX‐2/PGE2
released from cancer cells to this milieu suppresses host immuno-
logical responses to tumor‐derived antigens through blockade of the
activity for cytotoxic T lymphocytes (Miao et al., 2017). Another way
for COX‐2‐mediated immune resistance is through inducing indolea-
mine 2,3‐dioxygenase 1 in cancer cells (Hennequart et al., 2017;
Figure 3).
10 | COX ‐2 I S A ME DIATOR OF CANCER
CE LL GROW TH
There is a strong evidence for the contribution of COX‐2 in the
promotion of cancer cell growth (Raj et al., 2018). There are several
HASHEMI ET AL.
ways for COX‐2‐mediated cancer cell proliferation as follows: (a)
Induction of aromatase gene activity (aromatase cytochrome P450
[CYP19]; Esbona et al., 2018). Activation of CYP19 is contributed to
estrogen biosynthesis (Harris et al., 2007). COX‐2/PGE2 also induces
cytochrome P450 1B1 (CYP1B1) that is responsible for conversion of
the estrogen into estrogen quinones (Esbona et al., 2018) involved in
tumor mitogenic and proliferative features (Harris et al., 2007). (b)
Activation of neutrophils. COX‐2 derived from cancer cells is able to
activate neutrophils for the release of elastase relying proliferative
signals on cancer cells (Hattar et al., 2014; Figure 3). (c) Activation of
stromal CAFs. CAFs also send proliferative signals on cancer cells
(Hull et al., 2017; Figure 3). Finally, (d) inactivation of adhesion
molecules involved in regulation of cancer cell proliferation. An
example for these molecules is E‐cadherin that it makes a complex
with catenin (Noda et al., 2002).
11 | COX ‐2 I S A N I N H I B I T O R
OF APOPTO SIS I N CANCE R CELLS
COX‐2 is related to apoptosis suppression in many cancers. COX‐2
causes apoptosis resistance in cancer cells by making a delay in G1
phase (Gungor, Ilhan, & Eroksuz, 2018), induction of the expressions
for Survivin (Krysan, Dalwadi, Sharma, Põld, & Dubinett, 2004), Mcl‐2
(W. Chen et al., 2010) and Bcl‐2 (Hosseini et al., 2018; Todoric et al.,
2016), and repression of caspase‐3 (Janakiraman et al., 2017;
Figure 2).
The apoptosis mediator wild‐type p53 is a suppressor for COX‐2
expression (Mortezaee, 2018; Ohtsuka et al., 2018). In cancer cells,
however, mutations in the p53 occurs, so a positive‐feedback loop
between COX‐2 and the mutant p53 is an interesting event that
might be a target for chemotherapeutic agents (Chin et al., 2018;
Ohtsuka et al., 2018).
12 | COX ‐2 I S A M E D I A T O R O F T U M O R
MIGRATION, IN VA SION , AN D META STASIS
COX‐2 has been identified as one of the key metastasis progression
genes (Greenhough et al., 2009) involved in the metastasis into
lymph nodes (Höing et al., 2018), bone (Singh et al., 2006), liver
(Sorski et al., 2016), brain (Soto et al., 2016), and so forth. COX‐2
induces factors like IL‐11 that are related to cancer metastasis
(Singh et al., 2006). Epithelial–mesenchymal transition (EMT) in
cancer cells is a promoter of cancer invasiveness (Mortezaee, 2018).
COX‐2 induces EMT through increasing the activity for miR526b
(Majumder et al., 2015) and factors like signal transducer and
activator of transcription‐3 (STAT3; Tong et al., 2017), and that
inhibition of COX‐2‐mediated EMT occurs after application of
cannabinoids for cancer (Xian et al., 2016). COX‐2 also induces β1‐
integrin (Pan et al., 2016) and membrane proteases like matripase
that are responsible for cancer cell invasion (C. Ko et al.,
2017; Figure 2).
HASHEMI ET AL.
13 | COX ‐2 I S A M E D IA TO R
OF AN G I O G E NES I S I N C A N CE R
COX‐2 is expressed in tumor endothelial cells (Hull et al., 2017) and it is
related to an increase in the number of blood vessels in human cancers
(Montezuma et al., 2018) for cancer cell migratory purposes (Rüegg,
Dormond, & Mariotti, 2004; Figure 3). COX‐2 inhibitors like
c‐phycocyanin are able to suppress angiogenesis in cancer cells through
docking with VEGF (Jiang et al., 2018). Activation of COX‐2 for the
promotion of angiogenesis is induced by caspase‐3 (Feng et al., 2017;
Figure 2).
14 | COX ‐2 AS A N I N D UCE R O F C S C
AC TIVITY IN C ANC ER CE LLS
COX‐2 is identified to be implicated in maintenance of tissue resistance
CSC populations through promotion of CSC‐like properties including
tumorosphere formation, stemness, and metastatic propensity (C. Lu,
Eskandari, Cressey, & Suntharalingam, 2017). Inducible effect of COX‐2
on TGF‐β is related to the enrichment of CSCs (Tian et al., 2017).
Subcellular localization of COX‐2 within mitochondria favors mitochon-
drial recruitment (translocation) of p53 that in turn induces the activity
for mitochondrial fission Drp1 for the promotion of stemness (Zhou
et al., 2017). In addition, COX‐2 induces Id1 that serves as a marker of
CSC self‐renewal (Cook et al., 2016).
15 | MECHANISMS FOR C OX ‐2
CONTRIBUTION TO CANCER
PROGRE SSION
15.1 | Sirtuin (SIRT)/COX‐2
SIRT6 induces COX‐2 in cancer cells by suppressing AMPK (Yadav
et al., 2018). AMPK activation is a downstream target for the tumor
suppressor LKB1 (Gao, Ge, & Ji, 2011; Figure 4).
15.2 | NF‐κβ/COX‐2
NF‐κβ is contributed to activation of COX‐2 in both cancer cells
(Charalambous et al., 2003) and TAMs (Hung et al., 2004). There are
five related NF‐κβ proteins including p50 (NF‐κβ1), p52 (NF‐κβ2), p65
(RelA), RelB, and c‐Rel (Mortezaee, 2018), among them p65 has been
identified for its role in the activation of COX‐2 in cancer cells (Cai
et al., 2017; J. Hao et al., 2018). IKK and IkB are upstream signaling
molecules for NF‐κβ acting in its nuclear translocation (Mortezaee,
2018). NF‐κβ/COX‐2 could be a target for chemotherapeutic agents for
exerting their anticancer roles (H. Yang, Huang, et al., 2017). NF‐κβ/
COX‐2 signaling is induced by ERK1/2 (Wong et al., 2017), protein
kinase C (PKC; H.‐S. Baek et al., 2017), TRIP4 (J. Hao et al., 2018),
caspase‐3 (Feng et al., 2017), cytokines like interleukin 1β (IL‐1β;
Charalambous et al., 2003), and conditions like ER stress (Hung et al.,
2004). Inhibition of this signaling is mediated by miR‐16 (X. Liu, Li, Li,
et al., 2018) and annexin A5 (H.‐S. Baek et al., 2017; Figure 4).
| 7
15.3 | COX‐2/STAT3
COX‐2/STAT3 signaling is responsible for the promotion of an
immunosuppressive microenvironment (Maturu et al., 2017), EMT
(Tong et al., 2017), and proliferation (Ramu et al., 2018) of cancer
cells. This signaling could be a part of the extended NF‐κβ/COX‐2/
BCL‐2/IL‐6/STAT3 pathway (Das et al., 2017; Figure 2).
15.4 | PI3K/AKT/COX‐2
COX‐2 takes a role for activation of PI3K/AKT pathway by
suppressing phosphatase and tensin homologue (PTEN, an essential
tumor‐suppressing factor) in cancer cells either directly (Chang et al.,
2018) or indirectly through suppression of TET‐1‐induced PTEN
activation (H. Chen et al., 2017). MiR‐221/222 is able to block PTEN
resulting in activation of the PI3K/AKT/NF‐κβ/COX‐2 pathway (B. Li,
Lu, et al., 2017). Phosphoinositide 3‐kinase (PI3K) acts as both a
positive (Rundhaug & Fischer, 2008) or negative (W. Liu et al., 2003)
activator of COX‐2. Activation of COX‐2 by PI3K/AKT is mediated by
induction of NF‐κβ (B. Li, Lu, et al., 2017; Ramu et al., 2018).
Interestingly, PI3K also reduces binding activity of COX‐2 for NF‐κβ
(W. Liu et al., 2003; Figures 2 and 4).
15.5 | MAPK/COX‐2
Members of MAPK family including p38, ERK1/2, and c‐Jun NH2‐
terminal kinase are contributed to induction of COX‐2 (W. Liu et al.,
2003). ERK1/2 (Maturu et al., 2017) and p38 (Hu et al., 2017) are also
downstream targets for COX‐2. These MAPK members are mediator
of PKC inducible effects on COX‐2 in both cancer cells (Chou et al.,
2015) and CAFs (F. Li & Zhu, 2015). In addition, MAPK activity
mediates inducible activity of EGFR on COX‐2 (Dannenberg et al.,
2005; Hu et al., 2017) in which a possible interaction between EGFR/
p38 with COX‐2 favors angiogenesis in cancer cells (Hu et al., 2017).
P38/COX‐2 is also involved in cancer cell resistance to apoptosis
(Semaan et al., 2016; Figure 4).
15.6 | COX‐2/hypoxia inducible factor (HIF)
HIF‐1α is a marker of angiogenesis in cancer cells (Mortezaee, 2018)
and a target for COX‐2 (Maturu et al., 2017). An existing interplay
between COX‐2 and HIF‐1α is contributed to induction of hypoxia
within the TME. In the hypoxic conditions, HIF‐1α acts as a positive
inducer for COX‐2 expression (Greenhough et al., 2009). COX‐2/HIF‐
2α is associated with cancer cell resistance to chemotherapeutic
drugs in hypoxic conditions (Dong et al., 2018; Figure 2).
15.7 | Arylhydrocarbon receptor (AhR)/ARNT/
COX‐2
AhR interaction with its nuclear transporter ARNT is contributed to
the expression of COX‐2 and further production of PGE2 in cancer
cells (Ikeya et al., 2018; Figure 4).
8 |
15.8 | EGFR/COX‐2
There is a dual positive feedback between EGFR and COX‐2 in
cancer. This cross‐talk can amplify the process of carcinogenesis.
Tobacco smoking (Dannenberg et al., 2005; probably via its active
nicotine component; Dinicola et al., 2018) and ultraviolet light
(Fritsche et al., 2007) are among stimulators of this signaling. EGFR is
a downstream target for AhR signaling (Fritsche et al., 2007), and it is
also a part of the EGFR/COX‐2/Nodal pathway for cancer EMT and
CSC activity. Nodal is a member of TGF‐β superfamily (X. Wang,
Reyes, et al., 2017; Figures 2 and 4).
15.9 | SDF‐1/CXCR4/COX‐2
SDF‐1a is a member of CXC chemokine family that upon
interaction with its receptor CXCR4 and further stimulation of
COX‐2 is contributed to cancer cell invasion (N. Zheng, Chen, Liu,
et al., 2017) and metastasis (N. Zheng, Chen, Li, et al., 2017;
Figure 4).
15.10 | COX‐2/β‐catenin
β‐Catenin is another signaling for COX‐2/PGE2 to exert pro‐
oncogenic actions. This pathway is activated in lower stages of
cancer progression, and it is stimulated by factors like serpinB3
(Terrin et al., 2017; Figure 2).
16 | COX ‐2 AS A N A NTICA NC ER ENZY M E
COX‐2 acts a double‐edged sword by being as a pro‐ or
anticancer enzyme. COX‐2 is able to metabolize dihomo‐γ‐
linolenic acid into two different agents with diverse functions:
PGs and 8‐hydroxyoctanoic acid (8‐HOA; X. Yang, Xu, et al.,
2017). COX‐2 promotes tumor expansion through regulation of
PGs (Gurram et al., 2018). On the other hand, high level of COX‐2
can inhibit tumor growth and migration through regulation of 8‐
HOA (Y. Xu, Yang, et al., 2018; X. Yang, Xu, et al., 2017). Products
from COX‐2 can also exert both anti‐ and protumorigenic
functions. An example is the 15d‐PGJ2 acting as an anti‐ and
proangiogenic ligand (Ciccone, Monti, Monzani, Casella, &
Morbidelli, 2018; E.‐H. Kim & Surh, 2008). 15d‐PGJ2 is an
inducer for the proapoptotic peroxisome proliferator‐activated
receptor γ (PPARγ; Walther, Emmrich, Ramer, Mittag, & Hinz,
2016), while PGE2 is an inhibitor for this proapoptotic factor
(Rossi et al., 2018).
Depending on accumulation in which subcellular component, COX‐2
could be either a promoter or suppressor of cancer progression. This
would be best explained after application of resveratrol for cancer cells.
Transresveratrol is a component of the polyphenol extract and a stilbene
analog (Regulski et al., 2016) that acts on ERK1/2 (Lin et al., 2017) for
induction of nuclear accumulation (shuttling) of COX‐2. Nuclear shuttling
of ERK/COX‐2 complex favors p53 phosphorylation at Ser‐15 and the
HASHEMI ET AL.
F I G U R E 5 Cyclooxygenase‐2 (COX‐2) acting as an anticancer
enzyme. 8‐HOA: 8‐hydroxyoctanoic acid; DGLA: dihomo‐γ‐linolenic acid;
ERK1/2: extracellular signal‐regulated kinase‐1/2; PPARγ: peroxisome
proliferator‐activated receptor γ; ROS: reactive oxygen species
subsequent apoptosis in cancer cells (Chin et al., 2018). In addition,
resveratrol represses COX‐2 translocation to mitochondria to suppress
stemness in cacner cells (Zhou et al., 2017). Eventually, cytosolic
retention of COX‐2 leads to cancer cell proliferation mediated through
inhibition of the attachment between ERK and COX‐2 (Chin et al., 2018;
Lin et al., 2017).
For some tumors, COX‐2 inhibition is considered as a
disadvantage for cancer therapy. Overexpression of COX‐2 for
cancers like osteosarcoma (Z. Xu et al., 2006) favors the suppres-
sion of tumor proliferation and induction of apoptosis. Activation of
the P38/COX‐2 signaling (J.‐H. Baek et al., 2018) induces ROS
overproduction (Z. Xu et al., 2006) that is further contributed to
promotion of apoptosis in cancers like osteosarcoma. For glioma,
there are two opposite views for the roles of COX‐2 overexpression
with either enhancement of cancer promotion through interaction
between COX‐2 with NF‐κβ (X. Wang, Yu, et al., 2017; J. Zhao, Zhu,
et al., 2017), WNT (Wu et al., 2017), and EGFR (J. Li, Zhou, et al.,
2017) for respective induction of inflammation, CSC activity and
survival in cancer cells, or suppression of tumor progression
through possible interaction between COX‐2 with the endocanna-
binoid system that further elicits proapoptotic actions in this system
(Hinz, Ramer, Eichele, Weinzierl, & Brune, 2004). Evidence for
antitumor activity of COX‐2 has been shown in the Figure 5. A point
in this context is that the protumor activity of COX‐2 is far more
justifiable than its antitumor activity. Combining the knowledge
from Figures 6 to 8 in which COX‐2 overexpression is related to
tumorigenesis for a wide variety of cancers (Figure 6), targeting
COX‐2 expression in cancer cells is a common function of a variety
of chemotherapeutic agents (Figure 7), and COX‐2 induces multiple
HASHEMI ET AL. | 9

F I G U R E 6 Cancers known to overexpress cyclooxygenase‐2 (COX‐2). HNSCC: head and neck squamous cell carcinoma; LSCC: laryngeal
squamous cell carcinoma; NSCLC: non‐small‐cell lung cancer; OSCC: oral squamous cell carcinoma

F I G U R E 7 Agents identified for their chemopreventive roles against tumors working through cyclooxygenase‐2 (COX‐2) blockade in
cancer cells. ALG, α‐L‐guluronic acid; ALT: alantolactone; EA: Ellagic aicd; MC‐LR: microcystin‐LR; NSAIDs: nonsteroidal anti‐inflammatory
drugs; rcdtB: clostridium difficile toxin B; UA, uroslic acid

signaling in cancer cells for the promotion of cancer cell progression
(Figure 8), our justification toward the fate for COX‐2 would be
more into considering COX‐2 as a tumor promoter, rather than an
antitumor enzyme.
17 | HORMONES AFFE CT THE F ATE FOR
COX ‐2 EXP R E S S I O N D U RI N G TH E PROC ES S
TUMORIGENE SIS
A number of hormones are identified to have interactions with
COX‐2 for the promotion of tumorigenesis. Thyroxin (T4) stimulates
PD‐L1 to mediate cytoplasmic retention of COX‐2 that further blocks
the formation of ERK/COX‐2 complex resulting in proproliferative
features evolved in thyroid cancer cells (Chin et al., 2018; Lin et al.,
2017). Testosterone, DHT, suppresses ERK/COX‐2 and COX‐2/p53
complexes leading to proproliferative features in breast cancer cells
(Lin et al., 2017). Androgen inducible genes and androgen recep-
tors are also positively affected by COX‐2 (Brizzolara et al., 2017). In
addition, the existence of a positive‐feedback loop between estrogen
and COX‐2 favors aggravation of tumor‐promoting effect for this
hormone (Chung et al., 2017). Another hormone is epinephrine that
has been identified for its role in induction of COX‐2 and mediation
of an immunosuppressive state in cancer cells (Muthuswamy
et al., 2017).
18 | COX ‐2 I N H I B I T O R S AS A P R O M IS IN G
T H ER A P EU T I C AP P R O A C H F O R C A N C E R
Inhibition of COX‐2 could provide a high possibility to exert
therapeutic outcomes in cancer (Shi et al., 2018). Administration of
COX‐2 inhibitors for organs like lung, breast, colon, and prostate has
been attested to cause a reduction of cancer risk by about 68%
(Brizzolara et al., 2017). Interestingly, although it has been estimated
that about half of the adenomatic cancers do not express COX‐2
(Kashfi & Rigas, 2005; Noda et al., 2002), administration of COX‐2
inhibitors has shown promising results for suppression of adenoma
10 | HASHEMI
F I G U R E 8 A diagram revealing multitasking roles for
cyclooxygenase‐2 (COX‐2) in promotion of cancer. CSC: cancer
stem cell
development (Hull et al., 2017; Noda et al., 2002). For these types of
cancers, there is probably a shift for COX‐2 expression in stromal
(rather than cancer) cells (Hull et al., 2017).
COX‐2 inhibitors are relatively inexpensive in comparison with
the standard cancer therapies, having tolerable side effects, and that
they are able to sensitize cancer cells to treatments like radiotherapy
(Esbona et al., 2018) and chemotherapy (Shi et al., 2018) both of
which are recognized to induce COX‐2 expression in cancer cells
(Ikeya et al., 2018; Kirk et al., 2018). In fact, COX‐2 inhibitors are able
to relieve COX‐2‐mediated expression of multidrug resistance
proteins in cancer cells (Guo et al., 2017), and when they are
administered in a perioperative setting, the inhibitors would reduce
the risk of surgical related metastasis (Behrenbruch et al., 2018;
Shaashua et al., 2017). COX‐2 could be targeted by many types of
chemotherapeutic drugs, as it has been shown in the Figure 7.
Nonsteroidal anti‐inflammatory drugs (NSAIDs) are among the
drugs used for prevention of cancer. COX‐2 inhibition by NASIDs is
related to the reduction of cancer recurrence and increase of
patient survival (Esbona et al., 2018). Elevation of ROS concentra-
tion by NSAIDS is possibly accounted for inhibition of COX‐2 in
cancer cells (C. Lu, Laws, et al., 2017). Conventional NSAIDs are not
specific for inhibition of COX‐2, as they are also an inhibitor for
COX‐1, and that they irritate upper gastrointestinal (GI) system.
Example of these nonselective NSAIDs are ibuprofen (Liaras,
Fesatidou, & Geronikaki, 2018), sulindac (Dannenberg et al.,
2005), nimesulide (Barac et al., 2017), diclofenac, indomethacin,
and aspirin (J. Qiu et al., 2017). By contrast, the rate of injury to GI
using selective COX‐2 inhibitors is low (Dannenberg et al., 2005).
Coxibs (Lang et al., 2006; J. Qiu et al., 2017), etodolac (Noda et al.,
2002), and NS‐398 (J. Qiu et al., 2017) are examples for these
selective COX‐2 inhibitors (Lang et al., 2006; Figure 7). Recently,
ET AL.
copper‐bearing NSAIDs has been taken a special focus due to their
anti‐CSC properties (Eskandari et al., 2016).
Some NSAIDs like aspirin (Amaral, Nery, Leite, de Azevedo
Junior, & Campos, 2018) and celecoxib (J. Kim et al., 2018) depending
on the type of cancer could either inhibit or stimulate COX‐2
expression (Amaral et al., 2018), both of which favors apoptosis in
cancer cells. To explain, initial activation of COX‐2 by these inhibitors
may induce the proapoptotic factor PPARγ (Ramer et al., 2013), while
a late and extended deactivation of COX‐2 is probably required for
activation of PPARγ‐mediated apoptosis in cancer cells (Michael,
Badr, & Badawi, 2003; W.‐H. Sun et al., 2009). This deactivation could
blunt the inhibitory roles for COX‐2 metabolites like PGE2 on PPARγ
activity (Rossi et al., 2018). Therefore, COX‐2 inhibitors like celecoxib
although induce an initial expression for COX‐2 in cancers like lung,
this induction favors cancer cell apoptosis (Ramer et al., 2013).
Aspirin may also suppress growth of cancer cells via mechanisms
independent on COX‐2 (Henry et al., 2017).
COX‐2 could be a target for hormonal therapy. Melatonin, a
secretory product of pineal gland with diverse pharmacological
effects including anticancer activity (Mortezaee & Khanlarkhani,
2018; Mortezaee, Khanlarkhani, Beyer, & Zendedel, 2018), is an
example in this context showing promising results for suppression of
cancer progression by inhibiting NF‐κβ/COX‐2 signaling in cancer
cells (J.‐J. Lu et al., 2016; Mortezaee, 2018).
Application of miRNAs could be another approach for suppres-
sion of COX‐2 in cancer cells. MiRs 16 (X. Liu, Li, Li, et al., 2018), 101
(Y. Liu, Li, Zhao, & Jia, 2018), 379 (O’Brien et al., 2018), and 144 (Yao
et al., 2018) are identified for their role in suppression of COX‐2 in
cancer cells. COX‐2 could be an inducer of oncogenic miRs like
miR655 and miR526b in cancers like breast (Majumder et al.,
2018; Figure 4).
Another strategy for targeting COX‐2 in cancer cells is to use
carriers delivering siRNA for this enzyme. Agents like dextran
would do such work important for suppression of COX‐2 expres-
sion in cancer cells (Z. Chen, Krishnamachary, Penet, & Bhujwalla,
2018).
COX‐2 inhibitors provide a common target for exerting
synergistic therapeutic effects after combination with either
chemotherapeutic drugs (X. Xu et al., 2017) or chemoradiation
therapy (Das et al., 2017) against cancer cells. Chemotherapeutic
agents could adversely cause cancer cell repopulation through
induction of caspase‐3‐mediated COX‐2 activity (Y. Zhao, Cui,
et al., 2017). Irradiation is also an inducer of COX‐2‐mediated
angiogenesis through activation of the same pathway (Feng et al.,
2017). Some chemotherapeutic agents adversely induce COX‐2
expression indirectly via promotion of an inflammatory setting
(Kirk et al., 2018) probably through developing CAFs into
senescence CAFs by acquiring a proinflammatory SASP (Kabir
et al., 2016). Therefore, it would be advisable to use COX‐2
inhibitors as an adjuvant with chemotherapy and/or radiotherapy.
Such combination has been reported to synergistically increases
the antitumoral activity for chemotherapeutic agents like sorafe-
nib (Dong et al., 2018), 5‐fluorouracil, bleomycin, irinotecan (Shi
HASHEMI ET AL.
et al., 2018), cisplatin (Barac et al., 2017; F. Wang et al., 2018;
C.‐C. Yang et al., 2016), paclitaxel, carboplatin (Altorki et al.,
2003), sunitinib (Q. Zhao, Guo, Wang, Chu, & Hu, 2017), and
cetuximab (an EGFR blocker; Y. Lu, Shi, Qiu, & Fan, 2016) among
others. This combination also improves the rate of tolerance to
chemoradiation (Araujo‐Mino et al., 2018) and overall response
rate for advance stages of cancers (Dai et al., 2018), especially
when it is administered before radiotherapy (J. Qiu et al., 2017;
Salehifar & Hosseinimehr, 2016).
19 | F AC T O RS IN F LU E NC I NG
COX ‐2 ‐T A R G E T E D T H E R A P Y FO R C A N C E R
These factors are as follows:
(1) The type of cancer: Some types of cancers like schwannoma do not
respond to COX‐2 inhibitors despite its high rate of expression
(Wahle et al., 2018). In addition, cancer cells have their specific
activators for COX‐2, as for gastric cancer that the activator is
Helicobacter pylori (X. Liu et al., 2017) via JMJD2B (Han et al., 2016).
(2) The type of COX‐2 inhibitor: As for NSAIDSs, the response would
be more potent after application of selective drugs compared to
the non‐specific agents.
(3) The dose for COX‐2 inhibitors: High doses for COX‐2 inhibitors exert
opposite effects by showing anticancer activity (Shi et al., 2018). This
might be due to the effects of negative feedback loop or probably
upregulation of COX‐2 isoforms (Noda et al., 2002). To remove this
burden (decreasing the doses demanded for COX‐2 inhibitors), these
inhibitors are preferred to be administered in combination with
conventional anticancer agents (Shi et al., 2018).
(4) The type of chemotherapy (a conventional antitumor drug
received by patient) used in combination with COX‐2 inhibitors.
Choosing a right type of chemotherapy as an adjuvant with COX‐
2 inhibitor is also important.
(5) The grade of tumor: Relation between the grade of tumor with
COX‐2 expression is still a controversial issue. For example, two
studies performed on ovarian cancer were reached opposite
results with a one reported high expression for COX‐2 in the low
(mucus) grade (Beeghly‐Fadiel et al., 2018), but another the high
rate for COX‐2 in the high (serous) grade of cancer (Beeghly‐
Fadiel et al., 2018). This controversy has also been marked for
the breast cancer (Tury et al., 2016).
20 | CONC LU SION AN D P ERSP ECTIVE
From what has been discussed for most of the cancer types, COX‐2 is
a marker indicating worse prognosis and a stimulator for a variety of
cancers (Figure 6) by taking multitasking roles (Figure 8), so
suppression of COX‐2 could provide a promising approach for cancer
therapy especially when it is used as an adjuvant with appropriate
chemotherapeutic agents.
| 11
21 | S I GN IF IC AN CE
• Both activation and suppression of COX‐2 is related to tumorigenesis.
• COX‐2 activation could be both pro‐ or antitumorigenic, but the
evidence for its protumor activity is by far more strength.
• COX‐2 could be either activated or deactivated by ROS. This is
probably dependent on the concentration of ROS.
• For most type of cancers, uncontrolled activation of COX‐2 is
related to worse outcome and its blockade favors cancer
prophylaxis and regression.
• Most of the functions of COX‐2 on tumor cells is exerted through
engagement of PGE2/EP4, so targeting EP4 would provide an
optimistic approach for cancer therapy.
• Members of MAPK family, EGFR, and p65 NF‐κβ are major
regulators of COX‐2 in cancer cells. ERK acting on COX‐2 is
contributed to both pro‐ and antitumorigenic functions of COX‐2.
• Nuclear translocation of COX‐2 induces apoptosis in cancer cells,
while mitochondrial translocation of COX‐2 promotes stemness in
cancer cells.
• TME is a key for the promotion of COX‐2‐mediated tumorigenesis.
Production of COX‐2 occurs within this milieu. Macrophage type 2
cells, Tregs, and cancer cells are contributed to COX‐2 release to
the TME.
• Due to the complexity of signaling pathways contributed to the
regulation of COX‐2 in cancer cells and cancer cell resistance to
chemotherapy, it is preferred to use a combination of COX‐2
inhibitor with a suitable chemotherapeutic agent to achieve
appropriate responses.
• Existence of a negative feedback between COX‐2 and mediator of
apoptosis favors both apoptosis resistance and angiogenesis in
cancer cells.
CON F LI CTS OF I NTERE ST
The authors declare that there are no conflicts of interest.
ORCI D
Nasser Hashemi Goradel http://orcid.org/0000-0003-0713-1639
Keywan Mortezaee http://orcid.org/0000-0003-2004-3465
R E F E R E N CE S
Altorki, N. K., Keresztes, R., Port, J., Libby, D., Korst, R., Flieder, D., …
Pasmantier, M. (2003). Celecoxib, a selective cyclo‐oxygenase‐2
inhibitor, enhances the response to preoperative paclitaxel and
carboplatin in early‐stage non–small‐cell lung cancer. Journal of
Clinical Oncology, 21(14), 2645–2650.
Amaral, M. E. A., Nery, L. R., Leite, C. E., de Azevedo Junior, W. F., &
Campos, M. M. (2018). Pre‐clinical effects of metformin and aspirin on
the cell lines of different breast cancer subtypes. Investigational New
Drugs, 1–15.
Araki, Y., Okamura, S., Hussain, S. P., Nagashima, M., He, P., Shiseki, M., …
Harris, C. C. (2003). Regulation of cyclooxygenase‐2 expression by the
Wnt and ras pathways. Cancer Research, 63(3), 728–734.
12 | HASHEMI
Araujo‐Mino, E. P., Patt, Y. Z., Murray‐Krezan, C., Hanson, J. A., Bansal, P.,
Liem, B. J., … Lee, F. C. (2018). Phase II trial using a combination of
oxaliplatin, capecitabine, and celecoxib with concurrent radiation for
newly diagnosed resectable rectal cancer. The Oncologist, 23(1), 2–e5.
Baek, H.‐S., Park, N., Kwon, Y.‐J., Ye, D.‐J., Shin, S., & Chun, Y.‐J. (2017).
Annexin A5 suppresses cyclooxygenase‐2 expression by downregu-
lating the protein kinase C‐ζ–nuclear factor‐κB signaling pathway in
prostate cancer cells. Oncotarget, 8(43), 74263–74275.
Baek, J.‐H., Yim, J.‐H., Song, J.‐Y., Um, H.‐D., Park, J. K., Park, I.‐C., …
Hwang, S. G. (2018). Knockdown of end‐binding protein 1 induces
apoptosis in radioresistant A549 lung cancer cells via p38 kinase‐
dependent COX‐2 upregulation. Oncology Reports, 39(4),
1565–1572.
Barac, A., Mitulovic, G., Hallstrom, S., Zehetmayer, S., Grasl, M., & Erovic,
B. (2017). Impact of combined treatment with nimesulide and cisplatin
on oral carcinoma cells. OncoTargets and Therapy, 10, 3607–3616.
Beeghly‐Fadiel, A., Wilson, A. J., Keene, S., El Ramahi, M., Xu, S., Marnett,
L. J., … Khabele, D. (2018). Differential cyclooxygenase expression
levels and survival associations in type I and type II ovarian tumors.
Journal of Ovarian Research, 11(1), 17.
Behrenbruch, C., Shembrey, C., Paquet‐Fifield, S., Mølck, C., Cho, H.‐J.,
Michael, M., … Hollande, F. (2018). Surgical stress response and
promotion of metastasis in colorectal cancer: A complex and
heterogeneous process. Clinical & Experimental Metastasis, 35(4),
333–345.
Bohrer, L. R., Chaffee, T. S., Chuntova, P., Brady, N. J., Witschen, P. M.,
Kemp, S. E., … Schwertfeger, K. L. (2016). ADAM17 in tumor
associated leukocytes regulates inflammatory mediators and pro-
motes mammary tumor formation. Genes & Cancer, 7(7–8), 240–253.
Brizzolara, A., Benelli, R., Venè, R., Barboro, P., Poggi, A., Tosetti, F., &
Ferrari, N. (2017). The ErbB family and androgen receptor signaling
are targets of Celecoxib in prostate cancer. Cancer Letters, 400, 9–17.
Cai, T.‐T., Ye, S.‐B., Liu, Y.‐N., He, J., Chen, Q.‐Y., Mai, H.‐Q., … Li, J. (2017).
LMP1‐mediated glycolysis induces myeloid‐derived suppressor cell
expansion in nasopharyngeal carcinoma. PLoS Pathogens, 13(7),
e1006503.
Chang, J., Tang, N., Fang, Q., Zhu, K., Liu, L., Xiong, X., … Tao, J. (2018).
Inhibition of COX‐2 and 5‐LOX regulates the progression of colorectal
cancer by promoting PTEN and suppressing PI3K/AKT pathway.
Biochemical and Biophysical Research Communications. https://doi.org/
10.1016/j.bbrc.2018.01.061
Charalambous, M. P., Maihöfner, C., Bhambra, U., Lightfoot, T., &
Gooderham, N. J. (2003). Upregulation of cyclooxygenase‐2 is
accompanied by increased expression of nuclear factor‐κB and IκB
kinase‐α in human colorectal cancer epithelial cells. British Journal of
Cancer, 88(10), 1598–1604.
Chen, H., Cai, W., Chu, E. S. H., Tang, J., Wong, C. C., Wong, S. H., … Yu, J.
(2017). Hepatic cyclooxygenase‐2 overexpression induced sponta-
neous hepatocellular carcinoma formation in mice. Oncogene, 36(31),
4415–4426.
Chen, W., Bai, L., Wang, X., Xu, S., Belinsky, S. A., & Lin, Y. (2010). Acquired
activation of the Akt/cyclooxygenase‐2/Mcl‐1 pathway renders lung
cancer cells resistant to apoptosis. Molecular Pharmacology, 77(3),
416–423.
Chen, Z., Krishnamachary, B., Penet, M.‐F., & Bhujwalla, Z. M. (2018). Acid‐
degradable dextran as an image guided siRNA carrier for COX‐2
downregulation. Theranostics, 8(1), 1–12.
Cheng, H.‐H., Chu, L.‐Y., Chiang, L.‐Y., Chen, H.‐L., Kuo, C.‐C., & Wu, K. K.
(2016). Inhibition of cancer cell epithelial mesenchymal transition by
normal fibroblasts via production of 5‐methoxytryptophan. Oncotar-
get, 7(21), 31243.
Chin, Y.‐T., Wei, P.‐L., Ho, Y., Nana, A. W., Changou, C. A., Chen, Y.‐R., …
Lin, H. Y. (2018). Thyroxine inhibits resveratrol‐caused apoptosis by
PD‐L1 in ovarian cancer cells. Endocrine‐Related Cancer, 25(5),
533–545.
ET AL.
Chou, W. Y., Chuang, K. H., Sun, D., Lee, Y. H., Kao, P. H., Lin, Y. Y., … Wu,
Y. L. (2015). Inhibition of PKC‐induced COX‐2 and IL‐8 expression in
human breast cancer cells by glucosamine. Journal of Cellular
Physiology, 230(9), 2240–2251.
Chung, H. H., Or, Y. Z., Shrestha, S., Loh, J. T., Lim, C. L., Ong, Z., … Lin, V. C.
L. (2017). Estrogen reprograms the activity of neutrophils to foster
protumoral microenvironment during mammary involution. Scientific
Reports, 7, 46485.
Ciccone, V., Monti, M., Monzani, E., Casella, L., & Morbidelli, L. (2018). The
metal‐nonoate Ni (SalPipNONO) inhibits in vitro tumor growth,
invasiveness and angiogenesis. Oncotarget, 9(17), 13353.
Cook, P. J., Thomas, R., Kingsley, P. J., Shimizu, F., Montrose, D. C.,
Marnett, L. J., … Benezra, R. (2016). Cox‐2‐derived PGE2 induces Id1‐
dependent radiation resistance and self‐renewal in experimental
glioblastoma. Neuro‐Oncology, 18(10), 1379–1389.
Cui, Y., Shu, X. O., Li, H. L., Yang, G., Wen, W., Gao, Y. T., … Zheng, W.
(2017). Prospective study of urinary prostaglandin E2 metabolite and
pancreatic cancer risk. International Journal of Cancer, 141(12),
2423–2429.
Dai, P., Li, J., Ma, X.‐P., Huang, J., Meng, J.‐J., & Gong, P. (2018). Efficacy
and safety of COX‐2 inhibitors for advanced non‐small‐cell lung
cancer with chemotherapy: A meta‐analysis. OncoTargets and Therapy,
11, 721–730.
Dannenberg, A. J., Lippman, S. M., Mann, J. R., Subbaramaiah, K., & DuBois,
R. N. (2005). Cyclooxygenase‐2 and epidermal growth factor receptor:
Pharmacologic targets for chemoprevention. Journal of Clinical
Oncology, 23(2), 254–266.
Das, U., Biswas, S., Chattopadhyay, S., Chakraborty, A., Dey sharma, R.,
Banerji, A., & Dey, S. (2017). Radiosensitizing effect of ellagic acid on
growth of hepatocellular carcinoma cells: An in vitro study. Scientific
Reports, 7(1), 14043.
Desai, S. J., Prickril, B., & Rasooly, A. (2018). Mechanisms of Phytonutrient
Modulation of Cyclooxygenase‐2 (COX‐2) and Inflammation Related
to Cancer. Nutrition and Cancer, 70, 1–26.
Dinicola, S., Masiello, M. G., Proietti, S., Coluccia, P., Fabrizi, G.,
Catizone, A., … Cucina, A. (2018). Nicotine increases colon cancer
cell migration and invasion through epithelial to mesenchymal
transition (EMT): COX‐2 involvement. Journal of Cellular Physiol-
ogy, 233(6), 4935–4948.
Dong, Z.‐R., Dong, X.‐F., Liu, T.‐Q., Zhi, X.‐T., Zou, J., Zhong, J.‐T., …
Guo, W.‐W. (2018). COX‐2/PGE2 axis regulates HIF‐2α activity to
promote hepatocellular carcinoma hypoxic response and reduce
the sensitivity of sorafenib treatment. Clinical Cancer Research, 24,
3204–3216.
Echizen, K., Oshima, H., Nakayama, M., & Oshima, M. (2018). The
inflammatory microenvironment that promotes gastrointestinal can-
cer development and invasion. Advances in Biological Regulation, 68,
39–45.
Esbona, K., Inman, D., Saha, S., Jeffery, J., Schedin, P., Wilke, L., & Keely, P.
(2016). COX‐2 modulates mammary tumor progression in response to
collagen density. Breast Cancer Research, 18(1), 35.
Esbona, K., Yi, Y., Saha, S., Yu, M., Van Doorn, R. R., Conklin, M. W., …
Keely, P. J. (2018). The presence of cyclooxygenase 2, tumor‐
associated macrophages, and collagen alignment as prognostic
markers for invasive breast carcinoma patients. The American Journal
of Pathology, 188(3), 559–573.
Eskandari, A., Boodram, J. N., Cressey, P. B., Lu, C., Bruno, P. M., Hemann,
M. T., & Suntharalingam, K. (2016). The breast cancer stem cell
potency of copper (II) complexes bearing nonsteroidal anti‐inflamma-
tory drugs and their encapsulation using polymeric nanoparticles.
Dalton Transactions, 45(44), 17867–17873.
Feng, X., Yu, Y., He, S., Cheng, J., Gong, Y., Zhang, Z., … Huang, Q. (2017).
Dying glioma cells establish a proangiogenic microenvironment
through a caspase 3 dependent mechanism. Cancer Letters, 385,
12–20.
HASHEMI ET AL.
Fritsche, E., Schafer, C., Calles, C., Bernsmann, T., Bernshausen, T., Wurm, M., …
Krutmann, J. (2007). Lightening up the UV response by identification of
the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B
radiation. Proceedings of the National Academy of Sciences, 104(21),
8851–8856.
Furuya, H., Tamashiro, P. M., Shimizu, Y., Iino, K., Peres, R., Chen, R., …
Kawamori, T. (2017). Sphingosine Kinase 1 expression in peritoneal
macrophages is required for colon carcinogenesis. Carcinogenesis, 38
(12), 1218–1227.
Gan, L., Qiu, Z., Huang, J., Li, Y., Huang, H., Xiang, T., … Ren, G. (2016).
Cyclooxygenase‐2 in tumor‐associated macrophages promotes meta-
static potential of breast cancer cells through Akt pathway. Interna-
tional Journal of Biological Sciences, 12(12), 1533–1543.
Gao, Y., Ge, G., & Ji, H. (2011). LKB1 in lung cancerigenesis: A
serine/threonine kinase as tumor suppressor. Protein & Cell, 2(2),
99–107.
Genard, G., Wera, A.‐C., Huart, C., Le Calve, B., Penninckx, S., Fattaccioli, A., …
Michiels, C. (2018). Proton irradiation orchestrates macrophage
reprogramming through NFκB signaling. Cell Death & Disease, 9(7), 728.
Goswami, S., & Sharma‐Walia, N. (2016). Crosstalk between osteoprote-
gerin (OPG), fatty acid synthase (FASN) and, cycloxygenase‐2 (COX‐2)
in breast cancer: Implications in carcinogenesis. Oncotarget, 7(37),
58953.
Greenhough, A., Smartt, H. J. M., Moore, A. E., Roberts, H. R., Williams, A.
C., Paraskeva, C., & Kaidi, A. (2009). The COX‐2/PGE 2 pathway: Key
roles in the hallmarks of cancer and adaptation to the tumour
microenvironment. Carcinogenesis, 30(3), 377–386.
Gungor, H., Ilhan, N., & Eroksuz, H. (2018). The effectiveness of
cyclooxygenase‐2 inhibitors and evaluation of angiogenesis in the
model of experimental colorectal cancer. Biomedicine & Pharmacother-
apy, 102, 221–229.
Guo, Q., Liu, X., Lu, L., Yuan, H., Wang, Y., Chen, Z., … Zhou, Y. (2017).
Comprehensive evaluation of clinical efficacy and safety of celecoxib
combined with chemotherapy in management of gastric cancer.
Medicine, 96(51), e8857.
Gurram, B., Zhang, S., Li, M., Li, H., Xie, Y., Cui, H., … Peng, X. (2018).
Celecoxib conjugated fluorescent probe for identification and
discrimination of cyclooxygenase‐2 enzyme in cancer cells. Analytical
Chemistry, 90, 5187–5193.
Han, F., Ren, J., Zhang, J., Sun, Y., Ma, F., Liu, Z., … Li, W. (2016). JMJD2B is
required for Helicobacter pylori‐induced gastric carcinogenesis via
regulating COX‐2 expression. Oncotarget, 7(25), 38626.
Hao, J., Xu, H., Luo, M., Yu, W., Chen, M., Liao, Y., … Deng, W. (2018). The
tumor‐promoting role of TRIP4 in melanoma progression and its
involvement in response to BRAF‐targeted therapy. Journal of
Investigative Dermatology, 138(1), 159–170.
Hao, Y., Zhang, J., Shan, G., Zhang, N., Jin, W., & Nan, K. (2017). Establishment
of optimal regulatory network of colorectal cancer based on p42. 3
protein. Saudi Journal of Biological Sciences, 24, 1781–1786.
Harris, R. E., Beebe‐Donk, J., & Alshafie, G. A. (2007). Cancer
chemoprevention by cyclooxygenase 2 (COX‐2) blockade: Results of
case control studies, Subcellular Biochemistry, 42, 193–212.
Hattar, K., Franz, K., Ludwig, M., Sibelius, U., Wilhelm, J., Lohmeyer, J., …
Grandel, U. (2014). Interactions between neutrophils and non‐small
cell lung cancer cells: Enhancement of tumor proliferation and
inflammatory mediator synthesis. Cancer Immunology, Immunotherapy,
63(12), 1297–1306.
Hennequart, M., Pilotte, L., Cane, S., Hoffmann, D., Stroobant, V., Plaen, E.
D., & Eynde, B. J. V. (2017). Constitutive IDO1 expression in human
tumors is driven by cyclooxygenase‐2 and mediates intrinsic immune
resistance. Cancer Immunology Research, 5, 695–709.
Henry, W. S., Laszewski, T., Tsang, T., Beca, F., Beck, A. H., McAllister, S. S., &
Toker, A. (2017). Aspirin suppresses growth in PI3K‐mutant breast
cancer by activating AMPK and inhibiting mTORC1 signaling. Cancer
Research, 77(3), 790–801.
| 13
Hibino, S., Chikuma, S., Kondo, T., Ito, M., Nakatsukasa, H., Omata‐Mise, S.,
& Yoshimura, A. (2018). Inhibition of Nr4a receptors enhances anti‐
tumor immunity by breaking Treg‐mediated immune tolerance. Cancer
Research, 24, 3204–32016.
Higdon, A., Diers, A. R., Oh, J. Y., Landar, A., & Darley‐Usmar, V. M. (2012).
Cell signalling by reactive lipid species: New concepts and molecular
mechanisms. Biochemical Journal, 442(3), 453–464.
Hinz, B., Ramer, R., Eichele, K., Weinzierl, U., & Brune, K. (2004). Up‐
regulation of cyclooxygenase‐2 expression is involved in R (+)‐
methanandamide‐induced apoptotic death of human neuroglioma
cells. Molecular Pharmacology, 66(6), 1643–1651.
Hosseini, F., Mahdian‐Shakib, A., Jadidi‐Niaragh, F., Enderami, S. E.,
Mohammadi, H., Hemmatzadeh, M., … Mirshafiey, A. (2018). Anti‐
inflammatory and anti‐tumor effects of α‐l‐guluronic acid (G2013) on
cancer‐related inflammation in a murine breast cancer model.
Biomedicine & Pharmacotherapy, 98, 793–800.
Hou, P.‐C., Li, Y.‐H., Lin, S.‐C., Lin, S.‐C., Lee, J.‐C., Lin, B.‐W., … Tsai, S. J.
(2017). Hypoxia‐induced downregulation of DUSP‐2 phosphatase
drives colon cancer stemness. Cancer Research, 77(16), 4305–4316.
Hu, H., Han, T., Zhuo, M., Wu, L., Yuan, C., Wu, L., … Wang, L.‐W. (2017).
Elevated COX‐2 expression promotes angiogenesis through EGFR/
p38‐MAPK/Sp1‐dependent signalling in pancreatic cancer. Scientific
Reports, 7(1), 470.
Hull, M. A., Cuthbert, R. J., Ko, C. W. S., Scott, D. J., Cartwright, E. J.,
Hawcroft, G., … Coletta, P. L. (2017). Paracrine cyclooxygenase‐2
activity by macrophages drives colorectal adenoma progression in the
Apc Min/+mouse model of intestinal tumorigenesis. Scientific Reports,
7(1), 6074.
Hung, J.‐H., Su, I.‐J., Lei, H.‐Y., Wang, H.‐C., Lin, W.‐C., Chang, W.‐T., … Lai,
M. D. (2004). Endoplasmic reticulum stress stimulates the expression
of cyclooxygenase‐2 through activation of NF‐κB and pp38 mitogen‐
activated protein kinase. Journal of Biological Chemistry, 279(45),
46384–46392.
Höing, B., Kanaan, O., Altenhoff, P., Petri, R., Thangavelu, K., Schlüter, A., …
Brandau, S. (2018). Stromal versus tumoral inflammation differentially
contribute to metastasis and poor survival in laryngeal squamous cell
carcinoma. Oncotarget, 9(9), 8415.
Ikeya, S., Sakabe, J., Yamada, T., Naito, T., & Tokura, Y. (2018). Voriconazole‐
induced photocarcinogenesis is promoted by aryl hydrocarbon receptor‐
dependent COX‐2 upregulation. Scientific Reports, 8(1), 5050.
Janakiraman, H., House, R. P., Talwar, S., Courtney, S. M., Hazard, E. S.,
Hardiman, G., … Palanisamy, V. (2017). Repression of caspase‐3 and
RNA‐binding protein HuR cleavage by cyclooxygenase‐2 promotes
drug resistance in oral squamous cell carcinoma. Oncogene, 36(22),
3137–3148.
Jeong, A., Kim, J.‐H., Lee, H.‐J., & Kim, S.‐H. (2017). Reactive oxygen
species dependent phosphorylation of the liver kinase B1/AMP
activated protein kinase/acetyl‐CoA carboxylase signaling is critically
involved in apoptotic effect of lambertianic acid in hepatocellular
carcinoma cells. Oncotarget, 8(41), 70116.
Jiang, L., Wang, Y., Liu, G., Liu, H., Zhu, F., Ji, H., & Li, B. (2018). C‐
phycocyanin exerts anti‐cancer effects via the MAPK signaling
pathway in MDA‐MB‐231 cells. Cancer Cell International, 18(1), 12.
Kabir, T., Leigh, R., Tasena, H., Mellone, M., Coletta, R., Parkinson, E., …
Lambert, D. (2016). A miR‐335/COX‐2/PTEN axis regulates the
secretory phenotype of senescent cancer‐associated fibroblasts.
Aging, 8(8), 1608–1635.
Kashfi, K., & Rigas, B. (2005). Is COX‐2 a ‘collateral’ target in cancer
prevention? Biochemical Society Transactions, 33(Pt 4), 724–727.
Kim, J., Hong, S.‐W., Kim, S., Kim, D., Hur, D. Y., Jin, D.‐H., … Kim, Y. S.
(2018). Cyclooxygenase‐2 expression is induced by celecoxib treat-
ment in lung cancer cells and is transferred to neighbor cells via
exosomes. International Journal of Oncology, 52(2), 613–620.
Kim, E.‐H., Na, H.‐K., Kim, D.‐H., Park, S.‐A., Kim, H.‐N., Song, N.‐Y., & Surh,
Y.‐J. (2008). 15‐Deoxy‐Δ 12, 14‐prostaglandin J 2 induces COX‐2
14 | HASHEMI
expression through Akt‐driven AP‐1 activation in human breast
cancer cells: A potential role of ROS. Carcinogenesis, 29(4), 688–695.
Kim, E.‐H., & Surh, Y.‐J. (2008). The role of 15‐deoxy‐Δ12, 14‐
prostaglandin J2, an endogenous ligand of peroxisome proliferator‐
activated receptor γ, in tumor angiogenesis. Biochemical Pharmacology,
76(11), 1544–1553.
Kirk, J., Shah, N., Noll, B., Stevens, C. B., Lawler, M., Mougeot, F. B., &
Mougeot, J. L. C. (2018). Text mining‐based in silico drug discovery in
oral mucositis caused by high‐dose cancer therapy. Supportive Care in
Cancer, 26, 1–11.
Ko, C. J., Lan, S. W., Lu, Y. C., Cheng, T. S., Lai, P. F., Tsai, C. H., … Lee, M. S.
(2017). Inhibition of cyclooxygenase‐2‐mediated matriptase activa-
tion contributes to the suppression of prostate cancer cell motility
and metastasis. Oncogene, 36(32), 4597–4609.
Ko, S. C., Chapple, K. S., Hawcroft, G., Coletta, P. L., Markham, A. F., & Hull,
M. A. (2002). Paracrine cyclooxygenase‐2‐mediated signalling by
macrophages promotes tumorigenic progression of intestinal epithe-
lial cells. Oncogene, 21(47), 7175–7186.
Krishnamachary, B., Stasinopoulos, I., Kakkad, S., Penet, M.‐F., Jacob, D.,
Wildes, F., … Bhujwalla, Z. M. (2017). Breast cancer cell cyclooxygenase‐2
expression alters extracellular matrix structure and function and numbers
of cancer associated fibroblasts. Oncotarget, 8(11), 17981.
Krysan, K., Dalwadi, H., Sharma, S., Põld, M., & Dubinett, S. (2004).
Cyclooxygenase 2‐dependent expression of survivin is critical for
apoptosis resistance in non‐small cell lung cancer. Cancer Research, 64
(18), 6359–6362.
Lang, S., Busch, H., Boerries, M., Brummer, T., Timme, S., Lassmann, S., …
Schmidt, G. (2017). Specific role of RhoC in tumor invasion and
metastasis. Oncotarget, 8(50), 87364.
Lang, S., Picu, A., Hofmann, T., Andratschke, M., Mack, B., Moosmann, A., …
Zeidler, R. (2006). COX‐inhibitors relieve the immunosuppressive
effect of tumor cells and improve functions of immune effectors.
International Journal of Immunopathology and Pharmacology, 19(2),
409–419.
Lee, J., Ha, S. J., Park, J., Kim, Y. H., Lee, N. H., Kim, Y. E., … Jung, S. K.
(2017). 1, 8‐cineole prevents UVB‐induced skin carcinogenesis by
targeting the aryl hydrocarbon receptor. Oncotarget, 8(62), 105995.
Lee, J. H., Suh, J. H., Choi, S. Y., Kang, H. J., Lee, H. H., Ye, B. J., … Kwon, H.
M. (2018). Tonicity‐responsive enhancer‐binding protein promotes
hepatocellular carcinogenesis, recurrence and metastasis. Gut. gutjnl‐
2017‐315348. https://doi.org/10.1136/gutjnl-2017-315348
Li, W., Cao, Y., Xu, J., Wang, Y., Li, W., Wang, Q., … Sun, Y. (2017). YAP
transcriptionally regulates COX‐2 expression and GCCSysm‐4 (G‐4), a
dual YAP/COX‐2 inhibitor, overcomes drug resistance in colorectal
cancer. Journal of Experimental & Clinical Cancer Research, 36(1), 144.
Li, B., Lu, Y., Yu, L., Han, X., Wang, H., Mao, J., … Song, B. (2017). miR‐221/
222 promote cancer stem‐like cell properties and tumor growth of
breast cancer via targeting PTEN and sustained Akt/NF‐κB/COX‐2
activation. Chemico‐Biological Interactions, 277, 33–42.
Li, J., Zhou, Y., Wang, H., Gao, Y., Li, L., Hwang, S. H., … Hammock, B. D.
(2017). COX‐2/sEH dual inhibitor PTUPB suppresses glioblastoma
growth by targeting epidermal growth factor receptor and hyaluronan
mediated motility receptor. Oncotarget, 8(50), 87353.
Li, F., & Zhu, Y.‐T. (2015). HGF‐activated colonic fibroblasts mediates
carcinogenesis of colonic epithelial cancer cells via PKC‐cMET‐ERK1/
2‐COX‐2 signaling. Cellular Signalling, 27(4), 860–866.
Liaras, K., Fesatidou, M., & Geronikaki, A. (2018). Thiazoles and
thiazolidinones as COX/LOX inhibitors. Molecules, 23(3), 685.
Lin, H. Y., Hsieh, M. T., Cheng, G. Y., Lai, H. Y., Chin, Y. T., Shih, Y. J., …
Wang, K. (2017). Mechanisms of action of nonpeptide hormones on
resveratrol‐induced antiproliferation of cancer cells. Annals of the New
York Academy of Sciences, 1403, 92–100.
Liu, Y., Borchert, G. L., Surazynski, A., & Phang, J. M. (2008). Proline
oxidase, a p53‐induced gene, targets COX‐2/PGE 2 signaling to induce
ET AL.
apoptosis and inhibit tumor growth in colorectal cancers. Oncogene,
27(53), 6729–6737.
Liu, X., Ji, Q., Zhang, C., Liu, X., Liu, Y., Liu, N., … Li, Q. (2017). miR‐30a acts
as a tumor suppressor by double‐targeting COX‐2 and BCL9 in H.
pylori gastric cancer models. Scientific Reports, 7(1), 7113.
Liu, X., Li, S., Li, Y., Cheng, B., Tan, B., & Wang, G. (2018). Puerarin inhibits
proliferation and induces apoptosis by up‐regulation of miR‐16 in
bladder cancer cell line T24. Oncology Research.
Liu, Y., Li, H., Zhao, C., & Jia, H. (2018). MicroRNA‐101 inhibits
angiogenesis via COX‐2 in endometrial carcinoma. Molecular and
Cellular Biochemistry, 1–9. https://doi.org/10.1007/s11010-018-
3313-0
Liu, W., Reinmuth, N., Stoeltzing, O., Parikh, A. A., Tellez, C., Williams, S., …
Ellis, L. M. (2003). Cyclooxygenase‐2 is up‐regulated by interleukin‐1β
in human colorectal cancer cells via multiple signaling pathways.
Cancer Research, 63(13), 3632–3636.
Lu, C., Eskandari, A., Cressey, P. B., & Suntharalingam, K. (2017). Cancer
stem cell and bulk cancer cell active copper (II) complexes with
Vanillin Schiff base derivatives and naproxen. Chemistry‐A European
Journal, 23, 11366–11374.
Lu, C., Laws, K., Eskandari, A., & Suntharalingam, K. (2017). A reactive
oxygen species‐generating, cyclooxygenase‐2 inhibiting, cancer stem
cell‐potent tetranuclear copper (II) cluster. Dalton Transactions, 46(38),
12785–12789.
Lu, J.‐J., Fu, L., Tang, Z., Zhang, C., Qin, L., Wang, J., … Xie, F. (2016).
Melatonin inhibits AP‐2β/hTERT, NF‐κB/COX‐2 and Akt/ERK and
activates caspase/Cyto C signaling to enhance the antitumor activity
of berberine in lung cancer cells. Oncotarget, 7(3), 2985.
Lu, Y., Shi, C., Qiu, S., & Fan, Z. (2016). Identification and validation of
COX‐2 as a co‐target for overcoming cetuximab resistance in
colorectal cancer cells. Oncotarget, 7(40), 64766.
Majumder, M., Dunn, L., Liu, L., Hasan, A., Vincent, K., Brackstone, M., …
Lala, P. K. (2018). COX‐2 induces oncogenic micro RNA miR655 in
human breast cancer. Scientific Reports, 8(1), 327.
Majumder, M., Landman, E., Liu, L., Hess, D., & Lala, P. K. (2015). COX‐2
elevates oncogenic miR‐526b in breast cancer by EP4 activation.
Molecular Cancer Research, 13(6), 1022–1033.
Maturu, P., Jones, D., Ruteshouser, E. C., Hu, Q., Reynolds, J. M., Hicks, J.,
… Overwijk, W. W. (2017). Role of cyclooxygenase‐2 pathway in
creating an immunosuppressive microenvironment and in initiation
and progression of Wilms’ tumor. Neoplasia, 19(3), 237–249.
Miao, J., Lu, X., Hu, Y., Piao, C., Wu, X., Liu, X., … Liu, J. (2017).
Prostaglandin E2 and PD‐1 mediated inhibition of antitumor CTL
responses in the human tumor microenvironment. Oncotarget, 8(52),
89802.
Michael, M., Badr, M., & Badawi, A. (2003). Inhibition of cyclooxygenase‐2
and activation of peroxisome proliferator‐activated receptor‐γ syner-
gistically induces apoptosis and inhibits growth of human breast
cancer cells. International Journal of Molecular Medicine, 11(6),
733–736.
Montezuma, M. A. P., Fonseca, F. P., Benites, B. M., Soares, C. D., do
Amaral‐Silva, G. K., de Almeida, O. P., … Fregnani, E. R. (2018). COX‐2
as a determinant of lower disease‐free survival for patients affected
by ameloblastoma. Pathology, Research and Practice, 214, 907–913.
Mortezaee, K. (2018). Human hepatocellular carcinoma: Protection by
melatonin. Journal of Cellular Physiology, 233, 6486–6508.
Mortezaee, K., & Khanlarkhani, N. (2018). Melatonin application in
targeting oxidative‐induced liver injuries: A review. Journal of Cellular
Physiology, 233(5), 4015–4032.
Mortezaee, K., Khanlarkhani, N., Beyer, C., & Zendedel, A. (2018).
Inflammasome: Its role in traumatic brain and spinal cord injury.
Journal of Cellular Physiology, 233(7), 5160–5169.
Muthuswamy, R., Okada, N. J., Jenkins, F. J., McGuire, K., McAuliffe, P. F.,
Zeh, H. J., … Kalinski, P. (2017). Epinephrine promotes COX‐2‐dependent
HASHEMI ET AL.
immune suppression in myeloid cells and cancer tissues. Brain, Behavior,
and Immunity, 62, 78–86.
Nakanishi, Y., Nakatsuji, M., Seno, H., Ishizu, S., Akitake‐Kawano, R.,
Kanda, K., … Chiba, T. (2011). COX‐2 inhibition alters the phenotype
of tumor‐associated macrophages from M2 to M1 in Apc Min/+
mouse polyps. Carcinogenesis, 32(9), 1333–1339.
Noda, M., Tatsumi, Y., Tomizawa, M., Takama, T., Mitsufuji, S., Sugihara, H.,
… Hattori, T. (2002). Effects of etodolac, a selective cyclooxygenase‐2
inhibitor, on the expression of E‐cadherin‐catenin complexes in
gastrointestinal cell lines. Journal of Gastroenterology, 37(11),
896–904.
Obermoser, V., Baecker, D., Schuster, C., Braun, V., Kircher, B., & Gust, R.
(2018). Chlorinated cobalt alkyne complexes derived from acetylsa-
licylic acid as new specific antitumor agents. Dalton Transactions, 47
(12), 4341–4351.
O’Brien, K. P., Khan, S., Gilligan, K. E., Zafar, H., Lalor, P., Glynn, C., …
Dwyer, R. M. (2018). Employing mesenchymal stem cells to support
tumor‐targeted delivery of extracellular vesicle (EV)‐encapsulated
microRNA‐379. Oncogene, 37, 1–2149.
Ohtsuka, J., Oshima, H., Ezawa, I., Abe, R., Oshima, M., & Ohki, R. (2018).
Functional loss of p53 cooperates with the in vivo microenvironment
to promote malignant progression of gastric cancers. Scientific Reports,
8(1), 2291.
Pan, J., Yang, Q., Shao, J., Zhang, L., Ma, J., Wang, Y., … Bai, X. (2016).
Cyclooxygenase‐2 induced β1‐integrin expression in NSCLC and
promoted cell invasion via the EP1/MAPK/E2F‐1/FoxC2 signal
pathway. Scientific Reports, 6, 33823.
Pollock, J. K., Greene, L. M., Nathwani, S. M., Kinsella, P., O’Boyle, N. M.,
Meegan, M. J., & Zisterer, D. M. (2018). Involvement of NF‐κB in
mediating the anti‐tumour effects of combretastatins in T cells.
Investigational New Drugs, 36, 1–13.
Qiang, L., Sample, A., Shea, C. R., Soltani, K., Macleod, K. F., & He, Y.‐Y.
(2017). Autophagy gene ATG7 regulates ultraviolet radiation‐induced
inflammation and skin tumorigenesis. Autophagy, 13, 2086–2103.
Qin, G., Xu, F., Qin, T., Zheng, Q., Shi, D., Xia, W., … Wang, S. (2015).
Palbociclib inhibits epithelial‐mesenchymal transition and metastasis
in breast cancer via c‐Jun/COX‐2 signaling pathway. Oncotarget, 6(39),
41794.
Qiu, J., Shi, Z., & Jiang, J. (2017). Cyclooxygenase‐2 in glioblastoma
multiforme. Drug Discovery Today, 22(1), 148–156.
Qiu, H.‐Y., Wang, P.‐F., Li, Z., Ma, J.‐T., Wang, X.‐M., Yang, Y.‐H., & Zhu, H.‐
L. (2016). Synthesis of dihydropyrazole sulphonamide derivatives that
act as anti‐cancer agents through COX‐2 inhibition. Pharmacological
Research, 104, 86–96.
Raj, V., Bhadauria, A. S., Singh, A. K., Kumar, U., Rai, A., Keshari, A. K., …
Saha, S. (2018). Novel 1, 3, 4‐thiadiazoles inhibit colorectal cancer via
blockade of IL‐6/COX‐2 mediated JAK2/STAT3 signals as evidenced
through data‐based mathematical modeling. Cytokine. https://doi.org/
10.1016/j.cyto.2018.03.026
Ramer, R., Walther, U., Borchert, P., Laufer, S., Linnebacher, M., & Hinz, B.
(2013). Induction but not inhibition of COX‐2 confers human lung
cancer cell apoptosis by celecoxib. Journal of Lipid Research, 54(11),
3116–3129.
Ramu, A., Kathiresan, S., Ramadoss, H., Nallu, A., Kaliyan, R., & Azamuthu,
T. (2018). Gramine attenuates EGFR‐mediated inflammation and cell
proliferation in oral carcinogenesis via regulation of NF‐κB and STAT3
signaling. Biomedicine & Pharmacotherapy, 98, 523–530.
Regulski, M., Regulska, K., Prukała, W., Piotrowska, H., Stanisz, B., &
Murias, M. (2016). COX‐2 inhibitors: A novel strategy in the
management of breast cancer. Drug Discovery Today, 21(4), 598–615.
Rong, X., Huang, B., Qiu, S., Li, X., He, L., & Peng, Y. (2016). Tumor‐
associated macrophages induce vasculogenic mimicry of glioblastoma
multiforme through cyclooxygenase‐2 activation. Oncotarget, 7(51),
83976.
| 15
Rossi, E. L., Khatib, S. A., Doerstling, S. S., Bowers, L. W., Pruski, M., Ford,
N. A., … Hursting, S. D. (2018). Resveratrol inhibits obesity‐associated
adipose tissue dysfunction and tumor growth in a mouse model of
postmenopausal claudin‐low breast cancer. Molecular Carcinogenesis,
57(3), 393–407.
Rüegg, C., Dormond, O., & Mariotti, A. (2004). Endothelial cell integrins
and COX‐2: Mediators and therapeutic targets of tumor angiogenesis.
Biochimica et Biophysica Acta (BBA) – Reviews on Cancer, 1654(1),
51–67.
Rundhaug, J. E., & Fischer, S. M. (2008). Cyclo‐oxygenase‐2 plays a critical
role in UV‐induced skin carcinogenesis. Photochemistry and Photobiol-
ogy, 84(2), 322–329.
Salehifar, E., & Hosseinimehr, S. J. (2016). The use of cyclooxygenase‐2
inhibitors for improvement of efficacy of radiotherapy in cancers.
Drug Discovery Today, 21(4), 654–662.
Sample, A., Zhao, B., Qiang, L., & He, Y.‐Y. (2017). Adaptor protein p62
promotes skin tumor growth and metastasis and is induced by UVA
radiation. Journal of Biological Chemistry, 292(36), 14786–14795.
Semaan, J., Pinon, A., Rioux, B., Hassan, L., Limami, Y., Pouget, C., … Liagre, B.
(2016). Resistance to 3‐HTMC‐induced apoptosis through activation of
PI3K/Akt, MEK/ERK, and p38/COX‐2/PGE2 pathways in human HT‐29
and HCT116 colorectal cancer cells. Journal of Cellular Biochemistry, 117
(12), 2875–2885.
Shaashua, L., Shabat‐Simon, M., Haldar, R., Matzner, P., Zmora, O.,
Shabtai, M., … Ben‐Eliyahu, S. (2017). Perioperative COX‐2 and β‐
adrenergic blockade improves metastatic biomarkers in breast
cancer patients in a phase‐II randomized trial. Clinical Cancer
Research, 23, 4651–4661.
Sharma, S., Yang, S.‐C., Zhu, L., Reckamp, K., Gardner, B., Baratelli, F., …
Dubinett, S. M. (2005). Tumor cyclooxygenase‐2/prostaglandin E2–
dependent promotion of FOXP3 expression and CD4+CD25+T
regulatory cell activities in lung cancer. Cancer Research, 65(12),
5211–5220.
Shi, L., Xu, L., Wu, C., Xue, B., Jin, X., Yang, J., & Zhu, X. (2018). Celecoxib‐
induced self‐assembly of smart albumin‐doxorubicin conjugate for
enhanced cancer therapy. ACS Applied Materials & Interfaces, 10(10),
8555–8565.
Singh, B., Berry, J. A., Shoher, A., & Lucci, A. (2006). COX‐2 induces IL‐11
production in human breast cancer cells. Journal of Surgical Research,
131(2), 267–275.
Sorski, L., Melamed, R., Matzner, P., Lavon, H., Shaashua, L., Rosenne, E., &
Ben‐Eliyahu, S. (2016). Reducing liver metastases of colon cancer in
the context of extensive and minor surgeries through β‐adrenocep-
tors blockade and COX2 inhibition. Brain, Behavior, and Immunity, 58,
91–98.
Soto, M. S., O’brien, E. R., Andreou, K., Scrace, S. F., Zakaria, R.,
Jenkinson, M. D., … Sibson, N. R. (2016). Disruption of tumour‐host
communication by downregulation of LFA‐1 reduces COX‐2 and
e‐NOS expression and inhibits brain metastasis growth. Oncotarget,
7(32), 52375.
Su, C.‐W., Zhang, Y., & Zhu, Y.‐T. (2016). Stromal COX‐2 signaling are
correlated with colorectal cancer: A review. Critical Reviews in
Oncology/Hematology, 107, 33–38.
Sun, W.‐H., Chen, G.‐S., Ou, X.‐L., Yang, Y., Luo, C., Zhang, Y., … Ding, G. X.
(2009). Inhibition of COX‐2 and activation of peroxisome proliferator‐
activated receptor γ synergistically inhibits proliferation and induces
apoptosis of human pancreatic carcinoma cells. Cancer Letters, 275(2),
247–255.
Sun, H., Zhang, X., Sun, D., Jia, X., Xu, L., Qiao, Y., & Jin, Y. (2017). COX‐2
expression in ovarian cancer: An updated meta‐analysis. Oncotarget,
8(50), 88152.
Terrin, L., Agostini, M., Ruvoletto, M., Martini, A., Pucciarelli, S., Bettin, C.,
… Pontisso, P. (2017). SerpinB3 upregulates the Cyclooxygenase‐2/β‐
Catenin positive loop in colorectal cancer. Oncotarget, 8(9), 15732.
16 | HASHEMI
Theodoraki, M. N., Hoffmann, T., & Whiteside, T. (2018). Separation of
plasma‐derived exosomes into CD3 (+) and CD3 (–) fractions allows
for association of immune cell and tumour cell markers with disease
activity in HNSCC patients. Clinical & Experimental Immunology, 192,
271–283.
Tian, J., Hachim, M. Y., Hachim, I. Y., Dai, M., Lo, C., Raffa, F. A., … Lebrun, J.
J. (2017). Cyclooxygenase‐2 regulates TGFβ‐induced cancer stemness
in triple‐negative breast cancer. Scientific Reports, 7, 40258.
Tjiu, J.‐W., Chen, J.‐S., Shun, C.‐T., Lin, S.‐J., Liao, Y.‐H., Chu, C.‐Y., … Jee,
S. H. (2009). Tumor‐associated macrophage‐induced invasion and
angiogenesis of human basal cell carcinoma cells by cyclooxygen-
ase‐2 induction. Journal of Investigative Dermatology, 129(4),
1016–1025.
Todoric, J., Antonucci, L., & Karin, M. (2016). Targeting inflammation in cancer
prevention and therapy. Cancer Prevention Research, 9(12), 895–905.
Tong, D., Liu, Q., Liu, G., Xu, J., Lan, W., Jiang, Y., … Jiang, J. (2017).
Metformin inhibits castration‐induced EMT in prostate cancer by
repressing COX2/PGE2/STAT3 axis. Cancer Letters, 389, 23–32.
Tury, S., Becette, V., Assayag, F., Vacher, S., Benoist, C., Kamal, M., …
Callens, C. (2016). Combination of COX‐2 expression and PIK3CA
mutation as prognostic and predictive markers for celecoxib treat-
ment in breast cancer. Oncotarget, 7(51), 85124.
Wagner, T. M., Mullally, J. E., & Fitzpatrick, F. A. (2006). Reactive lipid
species from cyclooxygenase‐2 inactivate tumor suppressor LKB1/
STK11 cyclopentenone prostaglandins and 4‐hydroxy‐2‐nonenal
covalently modify and inhibit the AMP‐kinase kinase that modulates
cellular energy homeostasis and protein translation. Journal of
Biological Chemistry, 281(5), 2598–2604.
Wahle, B. M., Hawley, E. T., He, Y., Smith, A. E., Yuan, J., Masters, A. R., …
Yates, C. W. (2018). Chemopreventative celecoxib fails to prevent
schwannoma formation or sensorineural hearing loss in genetically
engineered murine model of neurofibromatosis type 2. Oncotarget, 9
(1), 718.
Walther, U., Emmrich, K., Ramer, R., Mittag, N., & Hinz, B. (2016).
Lovastatin lactone elicits human lung cancer cell apoptosis via a COX‐
2/PPARγ‐dependent pathway. Oncotarget, 7(9), 10345.
Wang, D., Buchanan, F. G., Wang, H., Dey, S. K., & DuBois, R. N. (2005).
Prostaglandin E2 enhances intestinal adenoma growth via activation
of the Ras‐mitogen‐activated protein kinase cascade. Cancer Research,
65(5), 1822–1829.
Wang, X., Reyes, M. E., Zhang, D., Funakoshi, Y., Trape, A. P., Gong, Y., … Ueno,
N. T. (2017). EGFR signaling promotes inflammation and cancer stem‐like
activity in inflammatory breast cancer. Oncotarget, 8(40), 67904.
Wang, X., Yu, Z., Wang, C., Cheng, W., Tian, X., Huo, X., … Xing, J. (2017).
Alantolactone, a natural sesquiterpene lactone, has potent antitumor
activity against glioblastoma by targeting IKKβ kinase activity and
interrupting NF‐κB/COX‐2‐mediated signaling cascades. Journal of
Experimental & Clinical Cancer Research, 36(1), 93.
Wang, F., Zhang, H., Ma, A.‐H., Yu, W., Zimmermann, M., Yang, J., … Pan, C. X.
(2018). COX‐2/sEH Dual Inhibitor PTUPB Potentiates the Antitumor
Efficacy of Cisplatin. Molecular Cancer Therapeutics, 17(2), 474–483.
Wang, J., Zou, K., Feng, X., Chen, M., Li, C., Tang, R., … Deng, W. (2017).
Downregulation of NMI promotes tumor growth and predicts poor
prognosis in human lung adenocarcinomas. Molecular Cancer, 16(1), 158.
Wong, J.‐H., Ho, K.‐H., Nam, S., Hsu, W.‐L., Lin, C.‐H., Chang, C.‐M., …
Chang, W.‐C. (2017). Store‐operated Ca 2+ entry facilitates the
lipopolysaccharide‐induced cyclooxygenase‐2 expression in gastric
cancer cells. Scientific Reports, 7(1), 12813.
Wu, M., Guan, J., Li, C., Gunter, S., Nusrat, L., Ng, S., … Das, S. (2017).
Aberrantly activated Cox‐2 and Wnt signaling interact to maintain
cancer stem cells in glioblastoma. Oncotarget, 8(47), 82217.
Xian, X., Huang, L., Zhang, B., Wu, C., Cui, J., & Wang, Z. (2016). WIN
55,212‐2 Inhibits the Epithelial Mesenchymal Transition of Gastric
Cancer Cells via COX‐2 Signals. Cellular Physiology and Biochemistry,
39(6), 2149–2157.
ET AL.
Xiang, W., Shi, R., Kang, X., Zhang, X., Chen, P., Zhang, L., … Miao, H.
(2018). Monoacylglycerol lipase regulates cannabinoid receptor 2‐
dependent macrophage activation and cancer progression. Nature
Communications, 9(1), 2574.
Xu, Z., Choudhary, S., Voznesensky, O., Mehrotra, M., Woodard, M.,
Hansen, M., … Pilbeam, C. (2006). Overexpression of COX‐2 in human
osteosarcoma cells decreases proliferation and increases apoptosis.
Cancer Research, 66(13), 6657–6664.
Xu, W., Huang, Y., Zhang, T., Zhao, L., Fan, J., & Li, L. (2018).
Cyclooxygenase‐2 gene polymorphisms and susceptibility to hepato-
cellular carcinoma: A meta‐analysis based on 10 case‐control studies.
Journal of Cancer Research and Therapeutics, 14(8), 105.
Xu, Y., Yang, X., Wang, T., Yang, L., He, Y.‐Y., Miskimins, K., & Qian, S. Y.
(2018). Knockdown delta‐5‐desaturase in breast cancer cells that
overexpress COX‐2 results in inhibition of growth, migration and
invasion via a dihomo‐γ‐linolenic acid peroxidation dependent
mechanism. BMC Cancer, 18(1), 330.
Xu, X., Zhu, G.‐Q., Zhang, K., Zhou, Y.‐C., Li, X.‐L., Xu, W., … Sun, W.‐H.
(2017). Cyclooxygenase‐2 mediated synergistic effect of ursolic acid
in combination with paclitaxel against human gastric carcinoma.
Oncotarget, 8(54), 92770.
Xuan, Y., Wang, J., Ban, L., Lu, J.‐J., Yi, C., Li, Z., … Deng, W. (2016).
hnRNPA2/B1 activates cyclooxygenase‐2 and promotes tumor
growth in human lung cancers. Molecular Oncology, 10(4), 610–624.
Yadav, D. K., Kumar, S., Saloni, S., Misra, S., Yadav, L., Teli, M., … Kim, M.
(2018). Molecular insights into the interaction of RONS and thieno [3,
2‐c] pyran analogs with SIRT6/COX‐2: A molecular dynamics study.
Scientific Reports, 8(1), 4777.
Yang, H., Huang, S., Wei, Y., Cao, S., Pi, C., Feng, T., … Ren, G. (2017).
Curcumin enhances the anticancer effect of 5‐fluorouracil against
gastric cancer through down‐regulation of COX‐2 and NF‐κB signaling
pathways. Journal of Cancer, 8(18), 3697–3706.
Yang, C.‐C., Tu, H.‐F., Wu, C.‐H., Chang, H.‐C., Chiang, W.‐F., Shih, N.‐C., …
Chang, K.‐W. (2016). Up‐regulation of HB‐EGF by the COX‐2/PGE2
signaling associates with the cisplatin resistance and tumor recur-
rence of advanced HNSCC. Oral Oncology, 56, 54–61.
Yang, X., Xu, Y., Wang, T., Shu, D., Guo, P., Miskimins, K., & Qian, S. Y.
(2017). Inhibition of cancer migration and invasion by knocking down
delta‐5‐desaturase in COX‐2 overexpressed cancer cells. Redox
Biology, 11, 653–662.
Yao, Q., Gu, A., Wang, Z., & Xue, Y. (2018). MicroRNA‐144 functions as a
tumor suppressor in gastric cancer by targeting cyclooxygenase‐2.
Experimental and Therapeutic Medicine, 15(3), 3088–3095.
Yue, X., Nguyen, T. D., Zellmer, V., Zhang, S., & Zorlutuna, P. (2018).
Stromal cell‐laden 3D hydrogel microwell arrays as tumor micro-
environment model for studying stiffness dependent stromal cell‐
cancer interactions. Biomaterials, 170, 37–48.
Zhao, Y., Cui, L., Pan, Y., Shao, D., Zheng, X., Zhang, F., … Chen, L. (2017).
Berberine inhibits the chemotherapy‐induced repopulation by sup-
pressing the arachidonic acid metabolic pathway and phosphorylation
of FAK in ovarian cancer. Cell Proliferation, 50(6), e12393.
Zhao, Q., Guo, J., Wang, G., Chu, Y., & Hu, X. (2017). Suppression of
immune regulatory cells with combined therapy of celecoxib and
sunitinib in renal cell carcinoma. Oncotarget, 8(1), 1668.
Zhao, J., Zhu, J., Lv, X., Xing, J., Liu, S., Chen, C., & Xu, Y. (2017). Curcumin
potentiates the potent antitumor activity of ACNU against glioblas-
toma by suppressing the PI3K/AKT and NF‐κB/COX‐2 signaling
pathways. OncoTargets and Therapy, 10, 5471–5482.
Zheng, N., Chen, J., Li, T., Liu, W., Liu, J., Chen, H., … Jia, L. (2017).
Abortifacient metapristone (RU486 derivative) interrupts CXCL12/
CXCR4 axis for ovarian metastatic chemoprevention. Molecular
Carcinogenesis, 56(8), 1896–1908.
Zheng, N., Chen, J., Liu, W., Liu, J., Li, T., Chen, H., … Jia, L. (2017).
Mifepristone inhibits ovarian cancer metastasis by intervening in
SDF‐1/CXCR4 chemokine axis. Oncotarget, 8(35), 59123.
HASHEMI ET AL. | 17

Zheng, X., Jia, B., Song, X., Kong, Q.‐Y., Wu, M.‐L., Qiu, Z.‐W., … Liu, J.
(2018). Preventive Potential of Resveratrol in Carcinogen‐Induced How to cite this article: Hashemi Goradel N, Najafi M, Salehi
Rat Thyroid Tumorigenesis. Nutrients, 10(3), 279. E, Farhood B, Mortezaee K. Cyclooxygenase‐2 in cancer: A
Zhou, T.‐J., Zhang, S.‐L., He, C.‐Y., Zhuang, Q.‐Y., Han, P.‐Y., Jiang, S.‐W., …
review. J Cell Physiol. 2018;1–17.
Lin, Z. N. (2017). Downregulation of mitochondrial cyclooxygenase‐2
inhibits the stemness of nasopharyngeal carcinoma by decreasing the https://doi.org/10.1002/jcp.27411
activity of dynamin‐related protein 1. Theranostics, 7(5), 1389–1406.