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Therapeutictargetsincancercell

metabolismandautophagy

NatureBiotechnology

30,

671-678

(2012)

doi:10.1038/nbt.2285

Publishedonline

10July2012

Abstract

Themetabolismofcancercellsisreprogrammedbothby

oncogenesignalingandbydysregulationofmetabolic

enzymes.Theresultingalteredmetabolismsupports

cellularproliferationandsurvivalbutleavescancercells

dependentonacontinuoussupplyofnutrients.Thus,

manymetabolicenzymeshavebecometargetsfornew

cancertherapies.Recently,twoprocesses—expressionof

specificisoformsofmetabolicenzymesand

autophagy—havebeenshowntobecrucialforthe

adaptationoftumorcellstochangesinnutrientavailability.

Anincreasingnumberofapprovedandexperimental

therapeuticstargetthesetwoprocesses.Abetter

understandingofthemolecularbasisofcancer-associated

metabolicchangesmayleadtoimprovedcancertherapies.

Activemetabolicpathwaysinproliferatingcellsinvolving

glucoseandglutaminecatabolismareinterconnectedand

linkedtomacromolecularsynthesisandenergybalance.

Keymetabolicenzymesdiscussedinthetext(shownin

blue)areactivelyinvestigatedastherapeutictargetsfor

cancertreatment.Metabolicenzymestargetedby

registeredagentsareshowninred.ACL,ATPcitratelyase;

aKG,a-ketoglutarate;DH,dehydrofolate;DHFR,

dehydrofolatereductase;dTMP,deoxythymidine

monophosphate;JUMP,deoxyuridinemonophosphate;

F-2,6-BP,fructose-2,6-bisphosphate;F6P,

fructose-6-phosphate;FBP,fructose-1,6-bisphosphate;FH,

fumaratehydratase;G6P,glucose-6-phosphate;GLS,

glutaminase;HK2,hexokinase2;IDH,isocitrate

dehydrogenase;LDHA,lactatedehydrogenaseA;MCT1,4,

monocarboxylatetransporter1,4;ME,malicenzyme;OAA,

oxaloacetate;PDH,pyruvatedehydrogenasecomplex;

PDK,pyruvatedehydrogenasekinase;PEP,

phosphoenolpyruvate;PFK,phosphofructokinase;PGAM,

phosphoglyceratemutase;PHGDH,phosphoglycerate

dehydrogenase;PKM2,pyruvatekinaseM2isoform;R5P,

ribose-5-phosphate;SDH,succinatedehydrogenase;TCA,

tricarboxylicacid;THF,tetrahydrofolate;TYMS,

thymidylatesynthase.

Seelarger

1.Figure2:Modulatorsoftheautophagypathway.

Variousgrowthandnutrientsignalingpathwaysare

associatedwithregulationofautophagy.Following

inhibitionofmTOR,theULK/Atg13/FIP200complexis

activatedandinitiatesautophagosome/phagophore

formation.TheclassIIIPI3kinase(Vps34)-Atg14L-Becn1

complexalsoregulatestheautophagosomenucleation

step.Toexpandtheautophagosomemembrane,two

ubiquitin-likeconjugationsystemsarerequiredfor

conjugationofLC3andAtg12tophosphatidyl

ethanolamine(PE)ontheautophagosomemembraneand

Atg5,respectively.Further,theAtg12-Atg5conjugate

interactswithAtg16,presumablylocatedonthesurfaceof

theautophagosomemembrane.Thecomplete

autophagosomefuseswiththelysosometoformthe

autolysosome,andcargomoleculesengulfedby

autophagosomesaredegradedbylysosomalhydrolases

andrecycledbacktothecytoplasm.Several

pharmacologicalinhibitors(red)modulatedistinctstepsof

autophagy.Someautophagyproteinswithenzymatic

activity(showningreenandyellow)couldbecrucialtarget

proteinsformodulationofautophagy.Pointswhere

inhibitorscouldbepotentiallydevelopedareshownas

blankboxes.CQ,chloroquine.

Introduction

Researchoverseveraldecadeshasidentifiedmany

oncogenesandtumorsuppressorsthatarefrequently

alteredinvarioustumors.Asubstantialproportionofthese

oncogenicabnormalitiesisassociatedwithgrowth

signalingpathways.Recently,increasingevidencehas

suggestedthatgrowthsignalingpathwaysdirectlycontrol

cellmetabolism,growthandproliferationthroughthe

regulationofmetabolicenzymes.Inaddition,individual

metabolicenzymeshavebeenreportedtobemutatedor

amplifiedduringtumorprogression.Understandinghow

metabolicpathwaysarealteredintumorsandhowcancer

cellsbenefitfromtumor-specificmetabolicchangesmay

contributetotheidentificationofnoveltherapeutictargets

andthedevelopmentofmoreeffectivecancertherapies.

Althoughalteredmetabolismisbeneficialtothecancercell,

itcancreateanincreaseddemandfornutrientstosupport

cellgrowthandproliferation.Atthesametime,theinner

massofatumormaylackadequatenutrientsbefore

sufficientangiogenesishasoccurred.Metabolicstressisa

stronginducerofautophagy,acatabolicprocessleadingto

degradationofcellularcomponentsthroughthelysosomal

system.Cancercellsuseautophagyasasurvivalstrategy

toprovideessentialbiomoleculesrequiredforcellviability

undermetabolicstress.Incontrast,basalautophagy

maintainsintracellularorganellehomeostasisby

eliminatingdamagedproteinsandorganelles,which

preventsgenerationofexcessreactiveoxygenspecies

(ROS)andgenomeinstability.Thus,autophagyisthought

tohaveakeyroleinthesuppressionoftumorigenesis.

Understandingthecontext-dependentroleofautophagyin

cancerdevelopmentshouldpresentnewopportunitiesfor

thedesignofcancertherapeutics.

Inthefirstsectionofthisreviewwesummarizerecent

progressinidentifyingenzymesthatcontributetothe

alteredmetabolismofcancercellsandinexploitingthese

enzymesastherapeutictargets.Inparticular,recent

findingsindicatethatalteredmetabolismincancercells

reliesonthepreferentialuseofalternativeisoformsof

enzymesorgenomicamplificationofenzymesinvolvedin

glucoseandaminoacidmetabolism.Inthesecondsection,

wediscusshowcancercellsadapttobioenergetic

challengesbyusingautophagyasacellsurvivalstrategy

andsummarizeongoingeffortstotargetautophagyin

combinationwithconventionalchemotherapy.

Metabolicenzymesalteredincancercells

Cancercellsmaintaintheirgrowthadvantagethrough

persistentactivationofgrowthsignalingpathwaysand

inactivationoftumorsuppressors.Canonicaloncogenic

signalingpathways,suchasphosphatidylinositol3-kinase

(PI3K)-AKT/ProteinKinaseB(PKB)andmammaliantarget

ofrapamycin(mTOR),directlyreprogramcorecarbon

metabolism,leadingtogreaternutrientuptakeandgreater

macromolecularbiosynthesistosupportcellproliferation.

Indeed,severalmetabolicenzymes,suchashexokinase2

(HK2),lactatedehydrogenaseA(LDHA)andpyruvate

dehydrogenasekinase1(PDK1),aredirecttargetsof

oncogenictranscriptionfactors,suchasMYCand

hypoxia-induciblefactor-1a(HIF-1a).Moreover,emerging

evidencesuggeststhatmetabolitesderivedfromaltered

metabolisminfluenceoncogenicsignalingpathwaysina

reciprocalmanner,andthatsuchinteractionsmaybethe

basisfortumorprogressionand/orresistanceto

conventionalchemotherapeuticapproaches.The

regulatoryconnectionsbetweensignalingpathwaysand

metabolicenzymeshavebeenextensivelyreviewed1,2.

Variousapproachestotargetoncogenicsignaling

pathwayshavebeenexploredforthepast20yearsand

haveshowngreatsuccessinclinicaltrials.Morerecently,

metabolicalterationsinvolvedincancerprogressionhave

becometargetsforpharmaceuticaldevelopment.Table1

liststhemetabolicenzymesthathavebeeninvestigatedin

oncologyclinicaltrials.Additionalmetabolicenzymesare

beingstudiedtodeterminetheirrolesintheprogressionof

variouscancersandtheirpotentialastherapeutictargets

(Fig.1).

Figure1:Coremetabolicpathwaysandmetabolic

enzymessuitableascancertherapeutictargets.

Glutamine

Activemetabolicpathwaysinproliferatingcellsinvolving

glucoseandglutaminecatabolismareinterconnectedand

linkedtomacromolecularsynthesisandenergybalance.

Keymetabolicenzymesdiscussedinthetext(shownin

blue)areactivelyinvestigatedastherapeutictargetsfor

cancertreatment.Metabolicenzymestargetedby

registeredagentsareshowninred.ACL,ATPcitratelyase;

aKG,a-ketoglutarate;DH,dehydrofolate;DHFR,

dehydrofolatereductase;dTMP,deoxythymidine

monophosphate;dUMP,deoxyuridinemonophosphate;

F-2,6-BP,fructose-2,6-bisphosphate;F6P,

fructose-6-phosphate;FBP,fructose-1,6-bisphosphate;FH,

fumaratehydratase;G6P,glucose-6-phosphate;GLS,

glutaminase;HK2,hexokinase2;IDH,isocitrate

dehydrogenase;LDHA,lactatedehydrogenaseA;MCT1,4,

monocarboxylatetransporter1,4;ME,malicenzyme;OAA,

oxaloacetate;PDH,pyruvatedehydrogenasecomplex;

PDK,pyruvatedehydrogenasekinase;PEP,

phosphoenolpyruvate;PFK,phosphofructokinase;PGAM,

phosphoglyceratemutase;PHGDH,phosphoglycerate

dehydrogenase;PKM2,pyruvatekinaseM2isoform;R5P,

ribose-5-phosphate;SDH,succinatedehydrogenase;TCA,

tricarboxylicacid;THF,tetrahydrofolate;TYMS,

thymidylatesynthase.

Table1:Potentialtherapeuticcompoundstargeting

metabolicenzymesoftumors

Glucosemetabolism.Inthe1920s,theGerman

biochemistOttoWarburgshowedthattumorcellsdiffer

fromnormalcellsintheirutilizationofglucose,an

observationthatisprobablythefirstevidenceofmetabolic

alterationsincancer3.Whereasnormalcellsdirectglucose

tomitochondrialoxidativephosphorylationtogenerate

ATPwhenoxygenisabundant,tumorcellsgenerally

exhibitgreaterglucoseuptake,glycolyticfluxandlactate

secretion,regardlessofoxygenavailability.This

phenomenon,calledaerobicglycolysis,formedthebasis

forthedevelopmentof18F-deoxyglucosepositronemission

tomographytoimagetumordevelopmentandregression

inpatients.Althoughtheroleandregulationofaerobic

glycolysisincancercellsarenotfullyunderstood,ithas

beensuggestedthatthisprocesssuppliesformsof

energeticandanabolicsubstratesthatfavormassive

macromolecularsynthesis.

UnderstandingoftheWarburgeffectspurredeffortsto

preferentiallyeliminatecancercellsbytargetingglucose

metabolism.Asglucoseenterscellsviaspecific

transporters,astraightforwardstrategywouldbetoblock

glucoseuptakebyinhibitingglucosetransporters.Atleast

onesmall-moleculeinhibitorofglucosetransporters

(silybin,alsoknownassilibinin)hasbeendeveloped,and

clinicaltrialsareongoingtotestitstoxicityandefficacy415.

However,asglucosetransportershaveseveralisoforms,

mostofwhicharehighlyexpressedincancercells,itwill

bechallengingtodevelopcompoundsthatinhibitall

isoformswithanacceptabletherapeuticwindow.

Analternativestrategyforinhibitingglucosemetabolism

reliesontheglucoseanalog2-deoxy-D-glucose.This

moleculeenterscellsviaglucosetransportersbutis

trappedas2-deoxyglucose-6-phosphateafter

phosphorylationbyhexokinaseandcannotbefurther

metabolized.Accumulationof

2-deoxyglucose-6-phosphateisthoughttoinhibitglycolytic

enzymesandglucosecatabolism.Although

2-deoxy-D-glucosehasbeeneffectiveinpreclinicaland

clinicalstudies,thistreatmenthasnotbeenfullyexplored

becauseofconcernsrelatedtopotentialtoxicityathigh

doses6.

Morerecently,ithasbeendiscoveredthatcancercells

seemtopreferentiallydependonspecificisoformsof

glycolyticenzymes6,promptingasearchfor

isoform-specificinhibitors,whichshouldincreasedrug

specificitytocancercellsandavoidtoxicitytonormalcells.

Keymetabolicpathwaysandenzymesbeinginvestigated

aspotentialtargetsincludethemuscle-specificisoformof

hexokinase2andphosphofructokinase2(Fig.1).

Tumor-specificexpressionoftheseisoformshasledto

identificationofisoform-specificinhibitorsthathave

substantiallysuppressedtumorgrowthinpreclinical

studies7,8andarebeingtestedclinically(Table1).

Arate-limitingstepinglycolysisisconversionof

phosphoenolpyruvatetopyruvateandgenerationofATP

bypyruvatekinase.Asplicingvariantofpyruvatekinase

foundinmuscle,PKM2,ispredominantlyexpressedin

embryoniccellsandtumorcells.Theglycolytic

intermediatefructose-1,6-bisphosphatebindstoPKM2and

convertsittoanenzymaticallyactiveform,whereasthe

tyrosinekinasesignalingpathwayinactivatesPKM2

throughthereleaseoffructose-1,6-bisphosphatefrom

PKM2(ref.9).Becausemostcancercellsexhibit

constitutivelyactivetyrosinekinasesignaling,theirlevelof

PKM2enzymeactivityislower.Thishasbeenproposedto

beimportantforcellproliferation,aslowPKM2activity

leadstoaccumulationofglycolyticintermediates,manyof

whicheitherareprecursorsofmacromolecularsynthesis,

suchasnucleotidesandaminoacids,orcanbeusedfor

generationofNADPH10.Laterstudieshavesuggestedthat

phosphoenolpyruvateactsasaphosphatedonorforthe

upstreamenzymephosphoglyceratemutasein

PKM2-expressingcells,whichfurtherpromotesglycolysis

andbiosyntheticprocesses11.Indeed,PKM2cellsmaintain

higherfluxtotheserinesyntheticpathway12.The

regulationofPKM2-mediatedserinesynthesismaybe

importantfortumorgrowthandmammaliantargetof

rapamycincomplex1(mTORCI)signaling(seebelow)12,13

Onthebasisofthesedata,avarietyofPKM2-specific

small-moleculeinhibitorsoractivatorshavebeen

investigatedfortheirtherapeuticpotentialinpreclinical

studies14,15,16,andsomearebeingtestedinclinicaltrials6

(Table1).

Generationanddisposaloflactate,theendproductof

glycolysis,hasbeenextensivelystudiedinconnectionwith

cancertherapy.Becauselactatedehydrogenaseconverts

pyruvatetolactatewhileoxidizingNADHtoNAD+to

supportcontinuedglycolyticflux,thisenzymehasbeen

consideredoneofthecriticaltargetsforsuppressing

elevatedglycolysis.LactatedehydrogenaseA(LDHA),an

isoformoflactatedehydrogenase,ispreferentially

expressedinmanycancersandisatranscriptionaltarget

ofMYCandHIF-1a.RNAinterference(RNAi)knockdown

experimentsinvariouscancercellshaveshownthatLDHA

hasanimportantroleintumorgrowth17,18119.Anatural

phenolderivative,gossypol,anditsderivativescompete

withNADHbindingtolactatedehydrogenaseandinhibit

lactatedehydrogenaseactivity.Despiteitslackof

specificity,gossypolisbeingtestedinclinicaltrialsfor

variouscancers20.Thegossypolanalogshavebeen

screenedforsmall-moleculeinhibitorsspecificforLDHA.

Amongthem,

3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthale

ne-1-carboxylicacid(FX11)effectivelyinhibitscancercell

growthinvitroandinvivobyincreasingoxidativestress21.

Morerecently,A/-hydroxyindole-basedcompoundshave

beenidentifiedasisoform-specificinhibitorsofLDHAthat

competewithitssubstratespyruvateandthecofactor

NADH22.

Pyruvatedehydrogenasekinase1(PDK1)isanother

transcriptionaltargetofMYCandHIF-1athatseemsto

haveacriticalroleinmanycancers.Itinactivatespyruvate

dehydrogenase,whichconvertspyruvatetoacetyl-CoAin

themitochondria.Asaresult,pyruvateisshuttledfromthe

tricarboxylicacidcycletoproducelactate.Accordingly,

specificinhibitorsofPDK1canblockaerobicglycolysis

andincreasetherateofoxidativephosphorylation.For

example,dichloroacetate,whichiswidelyusedforthe

treatmentoflacticacidosis,hasshownsuppressionof

tumorgrowthinpre-clinicalcancermodelsaswellasin

clinicaltrialsofprimaryglioblastoma23,24125(Table1),

althoughitsmechanismofactionrequiresfurther

investigationasitseemsthatthispyruvatemimetic

compoundlacksisoformselectivityamongPDKs.

Lactateaccumulatedinsidecancercellsisexported

throughthemonocarboxylatetransporterfamily.Impaired

functionofmonocarboxylatetransporterscauses

substantialdefectsincancercellproliferationandtumor

growth,indicatingthatcancercellsdependonefficient

lactatesecretion26127.Moreover,secretedlactatecanbe

takenupbyanisoformofmonocarboxylatetransporter,

MCT1,andusedasafuelsourcetosupportproliferationof

neighboringcellsthatarerelativelyoxidative.This

suggeststhatinthesametumor,cancercellswithdiverse

metabolicprofilesexchangetheirmetabolitesforsurvival

andgrowthinasymbioticmanner.Severalcompounds

thatblockthefunctionofMCT1arebeingdevelopedas

potentialcancertherapeutics28,29,30(Table1).

CompoundTargetTumortype/cancercelltypesClinical

stages

Glucosemetabolism

2-DGGlucosetransporterProstatecancerPhase1

Silybin/silibininProstatecancer(terminated)

Phase1/2

2-DGHK2ProstatecancerPhase1

Lonidamine(terminated)

Phase1

(Europe)

TLN-232/CAP-23PKM2Metastaticrenalcellcarcinoma,Phase2

melanoma

Gossypol/AT-101LDHAMultiplecancersPhase1/2

Dichloroacetate(DCA)PDKBraincancerPhase1

Non-smallcelllungcancerPhase2

Headandneckcancer

AZD3965MCT1AdvancedsolidtumorsPhase1/2

Nucleicacidmetabolism

MethotrexateFolatecycle(DHFR)MultiplecancersRegistered

Pemetrexed

5-FluorouracilThymidinesynthesis(TYMS)MultiplecancersRegistered

CompoundTargetTumortype/cancercelltypesClinical

stages

HydroxyureaDeoxynucleotidesynthesisMultiplecancersRegistered

(Ribonucleotidereductase:RNR)

Gemcitabine(Gemzar),Nucleotideincorporation(DNAMultiplecancersRegistered

Fludarabine(Fludara)polymerase/RNR)

Aminoacidmetabolism

-AsparginaseAsparagineLeukemiaRegistered

ArgininedeaminaseArginineMultiplecancersPhase2

(ADI-PEGconjugated)

NADmetabolism

FK866/APO866NicotinamideCutaneousT-celllymphoma

CHS828/GMX1777phosphoribosyl-transferase(CTCL),B-cellchronic

lymphocyticleukemia(CLL),

melanoma

Metastaticmelanoma,solid

tumors,lymphomas

Manycompoundstargetingglycolyticenzymeshave

synergisticanticancereffectsincombinationwith

conventionalchemotherapyorradiotherapyandwith

pathway-targetedagents.Atpresent,somecombinations

withagentstargetingglucosemetabolismhaveshown

promiseinclinicaltrials,andvariousenzymesinvolvedin

thereactionsbranchingfromglucosemetabolismthatare

alteredincancercellsarealsobeingactively

investigated31(Fig.1).

Glutaminemetabolism.Althoughtheinitialstudiesof

cancercellmetabolismfocusedonglucose,itisnowclear

thatmetabolismofaminoacidsandfattyacidsisalso

reprogrammedtoprovidethebuildingblocksforcancer

cellgrowthandproliferation.Glutamineisthemost

abundantaminoacidinthebloodandamajorsourceof

nitrogenforthesynthesisofnucleotides,aminoacidsand

glutathione.Inhighlyproliferativecells,itservesasa

carbonsourcetoreplenishthetricarboxylicacidcycleto

supportcellbioenergeticsandanabolicreactions.Several

groupshaverecentlyproposedthatcancercellsgrownin

hypoxicconditionsincreasetheirdependenceon

glutaminemetabolism,asglutamine-derived

a-ketoglutaratecanundergoreductivecarboxylationto

producecitrateandlipids32,33134.Therefore,glutamine

metabolisminhypoxiccancercellsseemstobean

essentialpathwayandanattractivetherapeutictarget.

Afterbeingtakenupbycells,glutamineisconvertedto

glutamatebythemitochondrialenzymeglutaminase.

Glutamateissubsequentlyconvertedtoa-ketoglutarateby

eitherglutamatedehydrogenaseoraminotransferases.As

anintermediateofthetricarboxylicacidcycle,

a-ketoglutaratecanprovidecarbonbackbonesforcellular

anabolicreactions35(Fig.1).Althoughtheoncogenic

signalingpathwaysinvolvedinrewiringglutamine

metabolismarenotfullyunderstood,multiplereportshave

suggestedthattheoncogenictranscriptionfactorMYC

controlsglutaminecatabolismbyregulatingexpressionof

glutaminetransportersandenzymesinvolvedin

glutaminolysis35136.Inaddition,MYC-overexpressingcells

aremarkedlysensitivetoglutaminedeprivation,

suggestingthattheyareaddictedtoglutamine35137.

Recently,Myc-inducedtumorigenesishasbeenassociated

withglutaminemetabolism,asshownbythecorrelation

betweenMycexpressionandthemetabolicprofilesof

mousetumors38.

Glutaminasehastwoisoforms.Glutaminase1(GLS1)is

thoughttobetheprimaryenzymeinvolvedin

glutaminolysis35,36,whereasGLS2seemstohavea

differentfunctionrelatedtotheantioxidantsystem39.

Recently,GLS1wasidentifiedusingunbiased

high-throughputscreeningasatargetofasmall-molecule

inhibitorthatblocksRho-GTPase-driventransformation40.

Moreover,anisoformofGLS1,glutaminaseC,is

consideredanimportanttargetowingtoitselevatedlevel

intumorsshowingglutamineaddiction.Recent

structure-basedstudiessuggestthatitsactivityis

regulatedbyinorganicphosphate,whichishighlyenriched

inmitochondriaunderhypoxia41,42.

Severalglutamineanalogs,includingthecompound

6-diazo-5-oxo-L-norleucine,havebeentestedas

therapeuticagentspreclinicallyandclinically.Although

treatmentwiththeseagentshasledtosubstantial

inhibitionofcancercellgrowthinvitroandinmouse

xenografts,thecompoundsarehighlytoxicowingtotheir

lackofspecificity43.Recently,aGLS1-specificinhibitor,

bis-2-(5-phenylacetimido-1,2,4,thiadiazol-2-yl)ethylsulfide

(BPTES),wasidentified44andshowntosubstantially

inhibitcancercellgrowthinvitroandinmousetumor

models38145.Asaselectiveinhibitor,BPTESmayachievea

largertherapeuticwindowthanglutamineanalogsbecause

specificinhibitionofGLS1wouldsuppressatumorrelying

onglutaminolysiswithoutaffectingotherimportant

functionsofglutamineinnormaltissues.

Anotherglutaminolysisenzyme,glutamatedehydrogenase,

isimportantforglioblastomacellsurvivalunderconditions

inwhichglucosecatabolismisimpairedortheAKT

pathwayisinhibited46.Epigallocatechingallate,apotent

andspecificinhibitorofglutamatedehydrogenase,blocks

glutaminolysisandsensitizesglioblastomacellstoglucose

deprivation46,47.Asglutaminecansupportcancercell

survivalunderglucoselimitationandhypoxia,the

suppressionofglutaminecatabolismwouldbesynergistic

withinhibitionofgrowthsignalingpathwaysrelatedto

glucosecatabolism.

Serinesyntheticpathways.Glycolyticintermediates

derivedfromenhancedglycolysisincancercellscanbe

shuntedtogeneratenonessentialaminoacids,lipidsand

nucleotidesthatfacilitatecancercellgrowthand

proliferation.Forexample,cellsexpressingPKM2

accumulatetheglycolyticintermediate3-phosphoglycerate,

whichcanbeshuntedtotheserinesyntheticpathway.As

aresult,PKM2cells(thatis,cancercells)canmaintain

mTORCIactivityandproliferationinserine-depleted

medium,whereasPKM1cells(thatis,normalcells)

cannot12,13.Notably,therate-limitingenzymeinvolvedin

branchingglycolysistotheserinesyntheticpathways,

phosphoglyceratedehydrogenase,isamplifiedinasubset

ofmelanomaandestrogenreceptor-negativebreast

cancer48,49,suggestingthatgreaterfluxintotheserine

syntheticpathwayprovidesselectiveadvantagetotumor

cells.Overexpressionofthisgeneleadstocellular

transformation,andRNAisuppressionofPHGDHleadsto

inhibitionofcancercellproliferationandtransformation48,49

Thereforephosphoglyceratedehydrogenaseisan

attractivemetabolictargetforcancertherapeutics,

togetherwithotherenzymesinvolvedintheserine

syntheticpathway.

Serineisanimportantnonessentialaminoacidthatcanbe

usedforsynthesisofotheraminoacids,suchasglycine

andcysteine,andforgenerationofphospholipids.In

addition,whenserineismetabolizedtoglycine,

tetrahydrofolateisconvertedto

5,10-methylene-tetrahydrofolate,acriticalstepin

maintainingthefolatecyclefornucleotidesynthesis50(Fig.

1).Thedependenceofcancercellsonthefolatecyclehas

beendemonstratedbysuccessfuldevelopmentof

antifolatedrugs,oneoftheearliestchemotherapies

developedinthelastcenturyandwidelyusedintheclinic

totreatvarioustypesofcancer(Table1).Examples

include5-fluorouracil,whichinhibitsthymidinesynthesis,

andmethotrexate,whichblockspurinesynthesisby

inhibitingdihydrofolatereductase,whichconverts

dihydrofolatetotetrahydrofolate(Table1).

Autophagy

Autophagyisaself-degradationprocesswherebycytosolic

componentsandorganellesaresequesteredindouble

membrane-boundvesiclesanddeliveredtolysosomesfor

degradationandrecycling(Fig.2).

PI3K/AktEnergy

Nutrients

Rapamycin

analogs

I—□