RE2IEW

cells in normal tissues +3, 4,% 5 e"amining how 6ouis Pasteur7s obser#ations regarding fermenta*tion of

Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation

In contrast to normal differentiated cells, which rel !rimaril on mitochondrial o"idati#e !hos!hor lation to generate the energ needed for cellular !rocesses, most cancer cells instead rel on aerobic gl col sis, a !henomenon termed $the Warburg effect%& 'erobic gl col sis is an inefficient wa to generate adenosine ()*tri!hos!hate +'TP,, howe#er, and the ad#antage it confers to cancer cells has been unclear% -ere we !ro!ose that the metabolism of cancer cells, and indeed all !roliferating cells, is ada!ted to facilitate the u!ta.e and incor!oration of nutrients into the biomass +e%g%, nucleotides, amino acids, and li!ids, needed to !roduce a new cell% /u!!orting this idea are recent studies showing that +i, se#eral signaling !athwa s im!licated in cell !roliferation also regulate metabolic !athwa s that incor!orate nutrients into biomass0 and that +ii, certain cancer*associated mutations enable cancer cells to acquire and metaboli1e nutrients in a manner conduci#e to !roliferation rather than efficient 'TP !roduction% ' better understanding of the mechanistic lin.s between cellular metabolism and growth control ma ultimatel lead to better treatments for human cancer%

glucose to ethanol might a!!l to mam*malian tissues, Warburg found that unli.e most normal tissues, cancer cells tend to $ferment& glucose into lactate e#en in the !resence of suf*ficient o" gen to su!!ort mitochondrial o"idati#e !hos!hor lation% ' definiti#e e"!lanation for Warburg7s obser#ation has remained elusi#e, at least in !art because the energ requirements of cell !roliferation a!!ear at first glance to be better met b com!lete catabolism of glucose using mito*chondrial o"idati#e !hos!hor lation to ma"imi1e adenosine ()*tri!hos!hate +'TP, !roduction%

In this re#iew, we e"!lore the metabolic

requirements of cell !roliferation in an attem!t to understand wh !roliferating cells metaboli1e glucose b aerobic gl col sis% 8nowledge of what !roliferating cells need in terms of energ to generate biomass will hel! illuminate the con* nection between signaling !athwa s that dri#e cell growth and the regulation of cell metabolism%

Proliferating Mammalian Cells E"hibit 'nabolic Metabolism

star#ation !eriod +:ig% ;,% Reflecting these fun* damental differences in metabolic needs, distinct regulator mechanisms ha#e e#ol#ed to control cellular metabolism in !roliferating #ersus non* !roliferating cells%
In multicellular organisms, most cells are e"*!osed to a constant su!!l of nutrients% /ur#i#al of the organism requires control s stems that !re#ent aberrant indi#idual cell !roliferation when nutrient a#ailabilit e"ceeds the le#els needed to su!!ort cell di#ision% Uncontrolled !roliferation is !re#ented because mammalian cells do not normall ta.e u! nutrients from their en#ironment unless stimulated to do so b growth factors% Cancer cells o#ercome this growth factor de!endence b acquiring genetic mutations that functionall alter rece!tor* initiated signaling !athwa s% There is growing e#idence that some of these !athwa s constituti#el acti#ate
;

Unicellular organisms
Abundant nutrients Scarce nutrients

Multicellular organisms
Abundant nutrients Growth signal

Proliferative metabolism

Starvation metabolism
Sugar

Proliferative metabolism
ATP
+

Sugar

Glucose
CO2

Biomass +
Ethanol/

organic acids
:ig% ;% Microbes and cells from multicellular organisms ha#e similar metabolic !henot !es under similar en#ironmental conditions% Unicellular organisms undergoing e"!onential growth often grow b fermentation of glucose into a small organic molecule such as ethanol% These organisms, and !roliferating cells in a multicellular organism, both metaboli1e glucose !rimaril through gl col sis, e"creting large amounts of carbon in the form of ethanol, lactate, or another organic acid such as acetate or but rate% Unicellular organisms star#ed of nutrients rel e#olutionar !rimaril on o"idati#e metabolism, as do cells in a multicellular organism that are not stimulated to !roliferate% This conser#ation suggests that there is an ad#antage to o"idati#e metabolism during nutrient limitation and nono"idati#e metabolism during cell !roliferation%

<e!artment of Medical 9ncolog , <ana*:arber Cancer Institute, 5oston, M' =>;;(, U/'% >5eth*Israel <eaconess Cancer Center and <e!artment of / stems 5iolog , -ar#ard Medical /chool, 5oston, M' =>;;(, U/'% 3<e!artment of Cancer 5iolog , 'bramson Cancer Center, Uni#ersit of Penns l#ania, Philadel!hia, P' ;?;=4, U/'% @To whom corres!ondence should be addressed: craigBmail%med%u!enn%edu E*mail: lewisAcantle Bhms%har#ard%edu0

RE2IEW
Differentiated tissue Proliferative tis su e
o r + O2 Glucose O2 Pyruvate Pyruvate
5% Lactate 85 %

Tumor

O2 Glucose O
2

+ / O2 Glucose

Pyruvate

con#erting two '<Ps to one 'TP and one 'MP +adenosine ()*mono!hos!hate,% This hel!s main*tain a #iable 'TPG'<P ratio as 'TP !roduction declines, but the accumulation of 'MP acti#ates 'MP*acti#ated !rotein .inase +'MP8,% This acti#ation is de!endent on the tumor su!!ressor !rotein 685; and leads to !hos!hor lation of se#eral targets to im!ro#e energ charge in cells +;4,% 685; was initiall identified as a tumor su!*!ressor gene, suggesting that the abilit to sense energ stress could be an im!ortant chec.!oint to !re#ent malignant transformation in some cell t !es% ' second !ossible e"!lanation for the switch to aerobic gl col sis, discussed in detail below, is that !roliferating cells ha#e im!ortant metabolic requirements that e"tend be ond 'TP%

Lactate Lactate

Crunching the CumbersHWhat 're the Metabolic Ceeds of Proliferating CellsI

To !roduce two #iable daughter cells at mitosis, a !roliferating cell must re!licate all of its cellular contents% This im!oses a large requirement for nucleotides, amino acids, and li!ids% <uring growth, glucose is used to generate biomass as well as !roduce 'TP% 'lthough 'TP h drol sis !ro#ides free energ for some of the biochemical reactions res!onsible for re!lication of biomass, these reac* tions ha#e additional requirements% :or instance, s nthesis of !almitate, a maJor constituent of cellular membranes, requires K molecules of 'TP, ;L car* bons from M molecules of acet l*Co' +coen1 me ',, and >M electrons from ;4 molecules of C'<PNnicotinamide adenine dinucleotide !hos!hate +C'<P ,, reducedO +M,% 6i.ewise, s nthesis of amino acids and nucleotides also consumes more equi#alents of carbon and C'<P- than of 'TP% '
D

CO2

CO2 Aero bic glycolysis (Warburg effect)

f r o m w w w % s c i e n c e m a g % o r g o n P u n e > , > = = ?
! r
g l

Oxidative phosphorylat ion

36 mol ATP/

Anaerobic glycolysis 2 mol ATP/ mol glucose

mol glucose

4 mol ATP/mol glucose

:ig% >% /chematic re!resentation of the differences between o"idati#e !hos!hor lation, anaerobic gl col sis, and aerobic gl col sis +Warburg effect,% In the !resence of o" gen, non!roliferating +differentiated, tissues first metaboli1e glucose to ! ru#ate #ia gl col sis and then com!letel o"idi1e most of that ! ru#ate in the mitochondria to C9> during the !rocess of o"idati#e !hos!hor lation% 5ecause o" gen is required as the final electron acce!tor to com!letel o"idi1e the glucose, o" gen is essential for this !rocess% When o" gen is limiting, cells can redirect the ! ru#ate generated b gl col sis awa from mitochondrial o"idati#e !hos!hor lation b generating lactate +anaerobic gl col sis,% This generation of lactate during anaerobic gl col sis allows gl col sis to continue +b c cling C'<- bac. to C'< ,, but results in minimal 'TP !roduction when com!ared with o"idati#e !hos!hor lation% Warburg obser#ed that cancer cells tend to con#ert most glucose to lactate regardless of whether o" gen is !resent +aerobic gl col sis,% This !ro!ert is shared b normal !roliferati#e tissues% Mitochondria remain functional and some o"idati#e !hos!hor lation continues in both cancer cells and normal !roliferating cells% Ce#ertheless, aerobic gl col sis is less efficient than o"idati#e !hos!hor lation for generating 'TP% In !roliferating cells, E;=F of the glucose is di#erted into bios nthetic !athwa s u!stream of ! ru#ate !roduction%
D

W h

: o

< o w n l o a d e d

;=3=
www%sciencemag%org

>> M'Q >==? 296 3>4 /CIECCE

counter to the needs of a !roliferating cell% /ome glucose must be di#erted to macromolecular !recursors such as acet l*Co' for fatt acids, gl col tic intermediates for nonessential amino acids, and ribose for nucleotides% This ma e"!lain at least !art of the selecti#e ad#antage !ro#ided b the Warburg effect, a h !othesis su!!orted b recent
;3

CHnuclear magnetic

resonance s!ectrosco*! measurements showing that glioblastoma cells in culture con#ert as much as ?=F of glucose and L=F of glutamine the acquire into lactate or alanine +;L,% 'lthough most of this lactate and alanine is e"creted from the cell as waste, one $b * !roduct& of their generation is a robust !roduction of C'<P- +:ig% 3,% In addition to !ro#iding nitro*gen for nonessential amino acids through transam*ination reactions, the catabolism of glutamine into lactate !roduces C'<P- #ia the acti#it of

C'<PD*s!ecific malate deh drogenase +malic en1 me,% Rrowth factor signaling also regulates the acti#it of the gl col tic en1 me ! ru#ate .inase and modulates flu" of carbon through the later ste!s of gl col sis +?, ;K,% This modulation of ! ru#ate .inase ma facilitate the redirection of glucose metabolites into the !entose !hos!hate shunt, as well as nucleotide and amino acid bios nthesis !athwa s% The con#ersion of both glucose and glutamine to lactate in#ol#es the en1 me lactate deh drogenase +6<-,% Inhibiting 6<- acti#it im!airs cell !roliferation +L,, !ossibl b interfering with the cell7s abilit to e"crete e"cess carbon% Elimination of e"cess carbon might be required to generate sufficient C'<P- to su!!ort cell !roliferation%
Most of the carbon for fatt acid s nthesis is deri#ed from glucose% <uring this !rocess, glucose

RE2IEW
is first con#erted to acet l*Co' in the mitochondrial matri" and used to s nthesi1e citrate in the TC' c cle% Under conditions of high 'TPG'<P and C'<-GC'<
D

e"hibited b most !roliferating cells, this citrate is e"creted bac. into the c tosol where li!ids are generated% In the c tosol, acet l*Co' is reca!tured from citrate and used as the carbon source for the growing ac l chains% / nthesis of acet l*Co' from citrate requires the en1 me 'TP citrate l ase +'C6,, and disru!tion of 'C6 im!airs tumor growth +;M,% Rlutamine u!ta.e also a!!ears to be critical for li!id s nthesis in that it su!!lies carbon in the form of mitochondrial o"aloacetate to maintain citrate !roduction in the first ste! of the TC' c cle +;L,% Thus, metabolism of both glutamine and glucose is orchestrated to su!!ort the !roduction of acet l*Co' and C'<P- needed for fatt acid s nthesis% :lu" of metabolites into

Glucos e Glucose

Growth factor stimulation

T
transpo rter Gluco se
Hexo-

kinase Glucose6-P

PI3K/A KT

Fructose6-P

AMP K

Phosph ofructo-

kinase

FB P

LKB 1
Glyceraldehyde3-P

PE

< o w n l o a d e d f r o m w w w % s c i e n c e m a g % o r g o n P u n e > , > = = ?

8e :ig% 3% Metabolic !athwa s acti#e in !roliferating cells are directl signaling and genes% shows gl col sis, !hos!hor lation, !entose !athwa , metabolism interconnected !roliferating both C'<Pcells% and tumor This our of controlled b !athwa s su!!ressor schematic current how the !hos!hate glutamine are in This o"idati#e ste!s b .nown for factor to both in these signaling to be cell rece!tors t rosine metabolic !athwa s can be influenced !athwa s im!ortant growth leads

able for macromolecular s nthesis as well as su!!orting C'<P!roduction% M c dri#es glutamine metabolism, which also su!!orts C'<P!roduction% 685;G'MP8 signaling and !(3 decrease metabolic flu" through gl col sis in res!onse to cell stress% <ecreased gl col tic flu" in res!onse to 685G'MP8 or !(3 ma be an ada!ti#e res!onse to shut off !roliferati#e metabolism during !eriods of low energ a#ailabilit or o"idati#e stress% Tumor su!!res*sors are shown

in red, and oncogenes are in green% 8e metabolic !ath*wa s are labeled in !ur!le with white bo"es, and the en1 mes controlling critical ste!s in these !athwa s are shown in blue% /ome of these en1 mes are candidates as no#el thera!eutic targets in cancer% Malic en1 me refers to C'<PD* s!ecific malate deh drogenase Ns stematic name +/,* malate:C'<PD o"idoreductase +o"aloacetate* decarbo" lating,O%

www%sciencemag%org /CIECCE 296 3>4 >> M'Q >==

in#ol#ing .nown oncogenes

!roliferation% 'cti#ation of

.inase signaling and PI38 acti#ation% 2ia '8T, PI38 acti#ation through the earl signaling late ste!s of stimulates !art of negati#el gl col sis, gl col tic glucose u!ta.e and flu" gl col sis% T rosine .inase regulates flu" through the ma.ing

understanding

metabolic wiring allows for !roduction and acet l*Co' flu" to the c tosol for li!id s nthesis%

intermediates a#ail*

RE2IEW
other s nthetic !athwa s for nucleic acid and amino acid s nthesis must be similarl balanced%
The e"cess generation of lactate that accom!anies the Warburg effect would a!!ear to be an inefficient use of cellular resources% Each lactate e"creted from the cell wastes three carbons that might otherwise be utili1ed for either 'TP !roduction or macromolecular !recursor bio*s nthesis% Possibl the dum!ing of e"cess carbon as lactate is effecti#e because it allows faster incor!oration of carbon into biomass, which in turn facilitates ra!id cell di#ision% :or most !roliferating cells, nutrients are not limiting so there is no selecti#e !ressure to o!timi1e metabolism for 'TP ield% In contrast, a selecti#e !ressure for rate of metabolism does e"ist% Immune :ig% 4% <ecreased metabolism of glucose b tumors, #isuali1ed b PET with the glucose analog :<R, !redicts res!onse to anticancer thera! % /hown are fused coronal images of :<R*PET and com!uteri1ed tomogra!h +CT, obtained on a h brid PETGCT scanner after the infusion of :<R in a !atient with a form of malignant sarcoma +gastrointestinal stromal tumor, before and after thera! with a t rosine .inase inhibitor +sunitinib,% The tumor +T, is readil #isuali1ed b :<R*PETGCT before thera! +left,% 'fter 4 wee.s of thera! +right,, the tumor shows no u!ta.e of :<R des!ite !ersistent abnormalities on CT% E"cess :<R is e"creted in the urine, and therefore the .idne s +8, and bladder +5, are also #isuali1ed as labeled% NImage courtes of '% <% 2an den 'bbeele, <ana*:arber Cancer Institute, 5ostonO res!onses and wound re!air de!end on the s!eed of the !roliferati#e e"!ansion of effector cells% To sur#i#e, the organism must signal the res!onding cells to ma"i* mi1e their rate of anabolic growth% Cells that con#ert glucose and gluta*mine into biomass most efficientl will !roliferate fastest% :or the or*ganism, nutrients ma be scarce and there are !athwa s acti#e in s!ecial*

cell cancer, !araganglioma, and !heochromoc toma +>4, >(,% 9ne effect of these mutations is acti#ation of -if;a*mediated glucose utili1ation +>L,% ' recent anal sis of human glioblastoma multiforme, an aggressi#e brain cancer, re#ealed that u! to ;>F of the tumors harbor the same !oint mutation in the gene encoding c tosolic isocitrate deh drogenaseH ; +I<-;, +>K,% Monoallelic mutation of the same residue in I<-;, or the analogous residue in the related en1 me I<->, is a common feature of gliomas as more than M=F of indolent gliomas harbor such a mutation +>M, >?,% I<-; and I<-> cou!le the intercon#ersion of c tosolic isocitrate and a*.etoglutarate in an C'<PDGC'<P-*de!endent reaction% What effect this mutation has on cellular metabolism is not clear0 howe#er, gi#en the im!ortant requirement for C'<P- in macro* molecular s nthesis and redo" control, alterations in C'<P!roduction ma affect cellular !rolif*

eration mutatio rates 'lter* nati#el such mutatio ma the !roduc citrate a* .etoglu as a c !recur macrom ular s nthe

Man

oncoge

t rosine

.inases feature

commo

t rosine

signalin with

associa

!rolifera

regulati

glucose

metabo

contras i1ed, non!roliferating tissues to rec cle the e"cess lactate and alanine dum!ed during the ra!id cell growth of !roliferating cells% The Cori c cle in the li#er can rec cle lactate generated from acti#el rec cle the alanine generated from !roliferating $inefficient& tissues to glucose, and analogous !athwa s e"ist to glutamine metabolism +M,% This abilit to rec cle the abilit to inhibit tumor :<R u!ta.e correlates with tumor regression +>;,% Rlucose withdrawal induces cell death in a manner indistinguishable from that seen u!on withdrawal of growth factor signaling, a !henomenon that ma contribute to $oncogene addiction& +>>,% Indeed, where it has been e"amined in cancer !atients, res!onse to thera! is !redicted b the abilit to disru!t glucose metabolism as measured b +:ig% 4,% :<R*PET +>3, cells, cells

differen

!rolifera

selecti#

e"!ress the

M> iso

organic waste !roduced b cell !roliferation during an immune res!onse or wound re!air results in a minimal im!act on the energ reser#es of the whole organism% In addition, there is emerging e#idence that cellular metabolism within a tumor can be heterogeneous, with some cells using the e"cess lactate generated as a fuel for mitochondrial o"idati#e !hos!hor lation +;?,%

gl

en1 me .inase

! ru#at

M>, +?, .inase M>

other !

isoform

Metabolic Regulation Is a Com!onent of the Cell Rrowth Machiner

The !hos!hoinositide 3*.inase +PI38, signaling !athwa is lin.ed to both growth control and glucose metabolism% In addition to a well*described role in directing a#ailable amino acids into !rotein s nthesis #ia mT9R, the PI38 !athwa regulates glucose u!ta.e and utili1ation +:ig% 3,% E#en in nonH insulin* de!endent tissues, PI38 signaling through '8T can regulate glucose trans!orter e"!ression, enhance glucose ca!ture b he"o.inase, and stimulate !hos!hofructo.inase acti#it +>,% PI38 !athwa acti#ation renders cells de!endent on high le#els of glucose flu" +>=,% /mall molecules that disru!t PI38 signaling lead to decreased glucose u!ta.e b tumors as measured b
;M

regulate

t rosine d +;K,% ne

!hos!h

Phos!h

down*st

of a #a nals the abilit

cell grow

negati#e M>

regulate

:*deo" glucose !ositron There is growing e#idence that metabolic en1 mes can directl contribute to carcinogenesis% Rermline mutations in the TC' c cle en1 mes succinate deh drogenase and fumarate h dratase ha#e been identified in some forms of human renal

emission tomogra!h +:<R*PET,, and the

+;K,%

res!ons

!hos!h

ne*!rote

binding,

M> is induced into a low*acti#it state% This regula* tion of en1 me acti#it ma consti*tute a molecular switch that allows cells to metaboli1e glucose through gl col sis in a manner that is con*sistent with !roliferating cell metabo*lism onl when growth signals are !resent +:ig% 3,% 'lthough counter* intuiti#e, it is the low*acti#it form of P8*M> that is necessar for cell !ro* liferation% This regulation allows P8*M> to act as a gate.ee!er that dictates the flow of carbon into bios nthetic !athwa s #ersus com!lete catabolism for 'TP !roduction% In su!!ort of this idea, P8* M> is required for !roliferation in #i#o +?,% -uman tumor cells whose growth is dri#en b oncogene are !articularl the MQC sensiti#e to gluta*mine withdrawal +3;,,

and genes in#ol#ed in glu*tamine metabolism a!!ear to be under both the direct and indirect transcri!tional control of the MQC !ro*tein +3>, 33,% Rlutamine de!letion from MQC*transformed cells results in the ra!id loss of TC' c cle intermediates and cell death +3;,% :urthermore, this de!endence on glutamine for sur#i#al is not related to the generation of 'TP b glutamine metabolism% Tumor su!!ressor !athwa s can also regulate cellular metabolism and ma act to coordinate nu*trient utili1ation with cell !h siolog % :or instance, !(3 e"!ression controls metabolic genes and alters glucose utili1ation% E"!ression of TIR'R, a gene induced b !(3, leads to inhibition of !hos!hofruc*to.inase, redirection of glucose toward the !entose !hos!hate shunt, and C'<P!roduction +34,% This ma be an ada!ti#e res!onse that !rotects the cell from o"idati#e stress, as C'<P- is required to generate the reduced form of glutathione, which is a maJor intracellular defense against damage medi*ated b reacti#e o" gen s!ecies +R9/,% Mitochondrial o"idati#e !hos!hor lation is the maJor cellular source of R9/ !roduction% Cells with e"cess nutrient u!ta.e that ha#e not con#erted to aerobic gl col sis would be !redicted to ha#e increased o"idati#e !hos!hor lation and R9/

;=3>
>> M'Q >==? 296 3>4 /CIECCE www%sciencemag%org

!roduction% This malada!ti#e metabolic state ma underlie the e#olutionar selection for induction of a!o!tosis andGor senescence in the setting of increased R9/% 5ecause some oncogenes dri#e glucose u!ta.e, this h !othesis ma e"!lain oncogene*induced senescence% :or instance, onco*genic Ras causes alterations in glucose metabolism +3(, but causes senescence when e"!ressed in cells without a coo!erating oncogene +3L,% :urther su!!orting this h !othesis is the obser#ation that stationar *!hase east lose #iabilit when e"!osed to high le#els of glucose and no additional nutrients +3K,% Qeast studies ha#e also demonstrated that o"idati#e !hos!hor lation sto!s during / !hase to limit R9/*mediated <C' damage, underscoring the im!ortance of limiting o"idati#e !hos!hor l*ation and R9/ !roduction in !roliferating cells +3M,%

What Triggers the /witch from 9"idati#e Phos!hor lation to 'erobic Rl col sisI
9ne !ro!osed e"!lanation for Warburg7s obser#a*tion is that tumor h !o"ia selects for cells de!en*dent on anaerobic metabolism +3?,% -owe#er, cancer cells a!!ear to use gl col tic metabolism before e"!osure to h !o"ic conditions% :or e"am*!le, leu.emic cells are highl gl col tic +4=, 4;,, et these cells reside within the bloodstream at higher o" gen tensions than cells in most normal tissues% /imilarl , lung tumors arising in the airwa s e"hibit aerobic gl col sis e#en though these tumor cells are e"!osed to o" gen during tumorigenesis +?, 4>,% Thus, although tumor h !o"ia is clearl im!ortant for other as!ects of cancer biolog , the a#ailable e#idence suggests that it is a late*occurring e#ent that ma not be a maJor contributor in the switch to aerobic gl col sis b cancer cells% The classic #iew of metabolism is that of a self*correcting, homeostatic s stem where a core set of house.ee!ing en1 mes enables the cell to res!ond to changing bioenergetic demands% -owe#er, as de*scribed abo#e, the e#ol#ing e#idence instead !oints to a d namicall regulated s stem that is !ro*grammed to fit the requirements for cell !roliferation or meet the s!ecific needs of each differentiated tissue as a!!ro!riate% :or normal !roliferating tis*sues, such as in the de#elo!ing embr o or during an immune res!onse in the adult, signals from growth factors allow cells to utili1e nutrients for growth +4;, 43,% Perha!s one function of oncogenic !ath*wa s is to dri#e cell*autonomous nutrient u!ta.e and !rogram !roliferati#e metabolism, whereas one function of tumor su!!ressor !athwa s is to !re#ent nutrient utili1ation for anabolic !rocesses% In this model, for cancer to arise, mutations are needed to gi#e cells the abilit to acquire nutrients and coordinatel regulate metabolic !athwa s to su!!ort !roliferation% This alteration in metabolic control ma result b re#erting to an embr onic !rogram, or e#ol#ing the ca!abilit to alter e"isting cell metabolism in a wa that su!!orts cell growth%

Cellular Metabolism and -uman Cancer

In !rinci!le, the metabolic de!endencies of cancer cells can be e"!loited for cancer treatment% :or instance, a large fraction of human cancer is de!endent on aberrant signaling through the PI38G'.t !athwa , and agents that target PI38 and #arious downstream signaling molecules are now in clinical trials% The growing e#idence that acti#ation of PI38 causes increased de!endenc on gl col sis suggests that these agents ma e"ert some of their effect b disru!ting glucose metabolism% <rugs targeting .e metabolic control !oints im!ortant for aerobic gl col sis, such as P8*M> or 6<-*', might also warrant in#estigation as !otential cancer thera!ies% In addition, the drugs de#elo!ed to target metabolic diseases such as t !e > diabetes ma ha#e use in treating cancer% ' number of retros!ecti#e clinical studies ha#e found that the widel used diabetes drug metformin ma offer a !ossible benefit in cancer !re#ention as well as im!ro#ed outcomes when used with other cancer thera!ies +44,% Metformin and the more !otent related com!ound Phenformin acti#ate 'MP8 in cells, suggesting that Phenformin or other acti#ators of 'MP8 might also be used as an adJunct to cancer thera! % 9!timal use of these drugs will require a better understanding of cancer cell metabolism and identification of the signaling !athwa s that re!resent an 'chilles7 heel for cell !roliferation or sur#i#al%

Metabolic tissues in mammals transform in*gested food into a near*constant su!!l of glucose, glutamine, and li!ids to balance the metabolic needs of both differentiated and !roliferating tis*sues% 'lterations in the a!!ro!riate balance of fuels andGor signal transduction !athwa s that deal with nutrient utili1ation ma underlie the cancer !redis*!osition associated with metabolic diseases such as diabetes and obesit +4(, 4L,% ' better understand*ing of how whole*bod metabolism interacts with tumor metabolism ma better define these ris.s and identif !otential !oints of thera!eutic inter#ention% In addition, it is !ossible that the cache"ia as*sociated with man cancers is e"acerbated b the e"cess nutrient consum!tion b the tumor, which would affect whole*bod metabolic regulation% To this end, the !otential role of dietar su!!lements and tight glucose control as adJuncts to cancer treatment is an acti#e field of in#estigation%

:uture Pros!ects
Metabolism is in#ol#ed directl or indirectl in essentiall e#er thing a cell does% There is mount*ing e#idence for cross*tal. between signaling !ath*wa s and metabolic control in e#er multicellular organism studied% There is still much to learn about how !roliferating cell metabolism is regulated% <es!ite a long and rich histor of research, the com!le" connection between metabolism and !ro*liferation remains an e"citing area of in#estigation% Indeed, new metabolic !athwa s ha#e been disco#*ered as recentl as the ;?M=s +4K,, and it is !ossible that additional !athwa s ha#e et to be described% Understanding this im!ortant as!ect of biolog is li.el to ha#e a maJor im!act on our understanding of cell !roliferation control and cancer%

RE2I EW
;=33