生物科学生物技术科技英语阅读精选1.docx

生物科学生物技术科技英语阅读精选1.docx

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生物科学生物技术科技英语阅读精选1

生物科学生物技术科技英语阅读精选

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Therapeutictargetsincancercellmetabolismandautophagy

Journalname:

NatureBiotechnology

Volume:

30,

Pages:

671–678

Yearpublished:

（2012）

DOI:

doi:

10.1038/nbt.2285

Publishedonline

10July2012

Abstract

Themetabolismofcancercellsisreprogrammedbothbyoncogenesignalingandbydysregulationofmetabolicenzymes.Theresultingalteredmetabolismsupportscellularproliferationandsurvivalbutleavescancercellsdependentonacontinuoussupplyofnutrients.Thus,manymetabolicenzymeshavebecometargetsfornewcancertherapies.Recently,twoprocesses—expressionofspecificisoformsofmetabolicenzymesandautophagy—havebeenshowntobecrucialfortheadaptationoftumorcellstochangesinnutrientavailability.Anincreasingnumberofapprovedandexperimentaltherapeuticstargetthesetwoprocesses.Abetterunderstandingofthemolecularbasisofcancer-associatedmetabolicchangesmayleadtoimprovedcancertherapies.

Activemetabolicpathwaysinproliferatingcellsinvolvingglucoseandglutaminecatabolismareinterconnectedandlinkedtomacromolecularsynthesisandenergybalance.Keymetabolicenzymesdiscussedinthetext（showninblue）areactivelyinvestigatedastherapeutictargetsforcancertreatment.Metabolicenzymestargetedbyregisteredagentsareshowninred.ACL,ATPcitratelyase;αKG,α-ketoglutarate;DH,dehydrofolate;DHFR,dehydrofolatereductase;dTMP,deoxythymidinemonophosphate;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,isocitratedehydrogenase;LDHA,lactatedehydrogenaseA;MCT1,4,monocarboxylatetransporter1,4;ME,malicenzyme;OAA,oxaloacetate;PDH,pyruvatedehydrogenasecomplex;PDK,pyruvatedehydrogenasekinase;PEP,phosphoenolpyruvate;PFK,phosphofructokinase;PGAM,phosphoglyceratemutase;PHGDH,phosphoglyceratedehydrogenase;PKM2,pyruvatekinaseM2isoform;R5P,ribose-5-phosphate;SDH,succinatedehydrogenase;TCA,tricarboxylicacid;THF,tetrahydrofolate;TYMS,thymidylatesynthase.

Seelarger

1.Figure2:

Modulatorsoftheautophagypathway.

Variousgrowthandnutrientsignalingpathwaysareassociatedwithregulationofautophagy.FollowinginhibitionofmTOR,theULK/Atg13/FIP200complexisactivatedandinitiatesautophagosome/phagophoreformation.TheclassIIIPI3kinase（Vps34）-Atg14L-Becn1complexalsoregulatestheautophagosomenucleationstep.Toexpandtheautophagosomemembrane,twoubiquitin-likeconjugationsystemsarerequiredforconjugationofLC3andAtg12tophosphatidylethanolamine（PE）ontheautophagosomemembraneandAtg5,respectively.Further,theAtg12-Atg5conjugateinteractswithAtg16,presumablylocatedonthesurfaceoftheautophagosomemembrane.Thecompleteautophagosomefuseswiththelysosometoformtheautolysosome,andcargomoleculesengulfedbyautophagosomesaredegradedbylysosomalhydrolasesandrecycledbacktothecytoplasm.Severalpharmacologicalinhibitors（red）modulatedistinctstepsofautophagy.Someautophagyproteinswithenzymaticactivity（showningreenandyellow）couldbecrucialtargetproteinsformodulationofautophagy.Pointswhereinhibitorscouldbepotentiallydevelopedareshownasblankboxes.CQ,chloroquine.

Introduction

Researchoverseveraldecadeshasidentifiedmanyoncogenesandtumorsuppressorsthatarefrequentlyalteredinvarioustumors.Asubstantialproportionoftheseoncogenicabnormalitiesisassociatedwithgrowthsignalingpathways.Recently,increasingevidencehassuggestedthatgrowthsignalingpathwaysdirectlycontrolcellmetabolism,growthandproliferationthroughtheregulationofmetabolicenzymes.Inaddition,individualmetabolicenzymeshavebeenreportedtobemutatedoramplifiedduringtumorprogression.Understandinghowmetabolicpathwaysarealteredintumorsandhowcancercellsbenefitfromtumor-specificmetabolicchangesmaycontributetotheidentificationofnoveltherapeutictargetsandthedevelopmentofmoreeffectivecancertherapies.

Althoughalteredmetabolismisbeneficialtothecancercell,itcancreateanincreaseddemandfornutrientstosupportcellgrowthandproliferation.Atthesametime,theinnermassofatumormaylackadequatenutrientsbeforesufficientangiogenesishasoccurred.Metabolicstressisastronginducerofautophagy,acatabolicprocessleadingtodegradationofcellularcomponentsthroughthelysosomalsystem.Cancercellsuseautophagyasasurvivalstrategytoprovideessentialbiomoleculesrequiredforcellviabilityundermetabolicstress.Incontrast,basalautophagymaintainsintracellularorganellehomeostasisbyeliminatingdamagedproteinsandorganelles,whichpreventsgenerationofexcessreactiveoxygenspecies（ROS）andgenomeinstability.Thus,autophagyisthoughttohaveakeyroleinthesuppressionoftumorigenesis.Understandingthecontext-dependentroleofautophagyincancerdevelopmentshouldpresentnewopportunitiesforthedesignofcancertherapeutics.

Inthefirstsectionofthisreviewwesummarizerecentprogressinidentifyingenzymesthatcontributetothealteredmetabolismofcancercellsandinexploitingtheseenzymesastherapeutictargets.Inparticular,recentfindingsindicatethatalteredmetabolismincancercellsreliesonthepreferentialuseofalternativeisoformsofenzymesorgenomicamplificationofenzymesinvolvedinglucoseandaminoacidmetabolism.Inthesecondsection,wediscusshowcancercellsadapttobioenergeticchallengesbyusingautophagyasacellsurvivalstrategyandsummarizeongoingeffortstotargetautophagyincombinationwithconventionalchemotherapy.

Metabolicenzymesalteredincancercells

Cancercellsmaintaintheirgrowthadvantagethroughpersistentactivationofgrowthsignalingpathwaysandinactivationoftumorsuppressors.Canonicaloncogenicsignalingpathways,suchasphosphatidylinositol3−kinase（PI3K）-AKT/ProteinKinaseB（PKB）andmammaliantargetofrapamycin（mTOR）,directlyreprogramcorecarbonmetabolism,leadingtogreaternutrientuptakeandgreatermacromolecularbiosynthesistosupportcellproliferation.Indeed,severalmetabolicenzymes,suchashexokinase2（HK2）,lactatedehydrogenaseA（LDHA）andpyruvatedehydrogenasekinase1（PDK1）,aredirecttargetsofoncogenictranscriptionfactors,suchasMYCandhypoxia-induciblefactor-1α（HIF-1α）.Moreover,emergingevidencesuggeststhatmetabolitesderivedfromalteredmetabolisminfluenceoncogenicsignalingpathwaysinareciprocalmanner,andthatsuchinteractionsmaybethebasisfortumorprogressionand/orresistancetoconventionalchemotherapeuticapproaches.Theregulatoryconnectionsbetweensignalingpathwaysandmetabolicenzymeshavebeenextensivelyreviewed1,2.

Variousapproachestotargetoncogenicsignalingpathwayshavebeenexploredforthepast20yearsandhaveshowngreatsuccessinclinicaltrials.Morerecently,metabolicalterationsinvolvedincancerprogressionhavebecometargetsforpharmaceuticaldevelopment.Table1liststhemetabolicenzymesthathavebeeninvestigatedinoncologyclinicaltrials.Additionalmetabolicenzymesarebeingstudiedtodeterminetheirrolesintheprogressionofvariouscancersandtheirpotentialastherapeutictargets（Fig.1）.

Figure1:

Coremetabolicpathwaysandmetabolicenzymessuitableascancertherapeutictargets.

Activemetabolicpathwaysinproliferatingcellsinvolvingglucoseandglutaminecatabolismareinterconnectedandlinkedtomacromolecularsynthesisandenergybalance.Keymetabolicenzymesdiscussedinthetext（showninblue）areactivelyinvestigatedastherapeutictargetsforcancertreatment.Metabolicenzymestargetedbyregisteredagentsareshowninred.ACL,ATPcitratelyase;αKG,α-ketoglutarate;DH,dehydrofolate;DHFR,dehydrofolatereductase;dTMP,deoxythymidinemonophosphate;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,isocitratedehydrogenase;LDHA,lactatedehydrogenaseA;MCT1,4,monocarboxylatetransporter1,4;ME,malicenzyme;OAA,oxaloacetate;PDH,pyruvatedehydrogenasecomplex;PDK,pyruvatedehydrogenasekinase;PEP,phosphoenolpyruvate;PFK,phosphofructokinase;PGAM,phosphoglyceratemutase;PHGDH,phosphoglyceratedehydrogenase;PKM2,pyruvatekinaseM2isoform;R5P,ribose-5-phosphate;SDH,succinatedehydrogenase;TCA,tricarboxylicacid;THF,tetrahydrofolate;TYMS,thymidylatesynthase.

Table1:

Potentialtherapeuticcompoundstargetingmetabolicenzymesoftumors

Glucosemetabolism.Inthe1920s,theGermanbiochemistOttoWarburgshowedthattumorcellsdifferfromnormalcellsintheirutilizationofglucose,anobservationthatisprobablythefirstevidenceofmetabolicalterationsincancer3.WhereasnormalcellsdirectglucosetomitochondrialoxidativephosphorylationtogenerateATPwhenoxygenisabundant,tumorcellsgenerallyexhibitgreaterglucoseuptake,glycolyticfluxandlactatesecretion,regardlessofoxygenavailability.Thisphenomenon,calledaerobicglycolysis,formedthebasisforthedevelopmentof18F-deoxyglucosepositronemissiontomographytoimagetumordevelopmentandregressioninpatients.Althoughtheroleandregulationofaerobicglycolysisincancercellsarenotfullyunderstood,ithasbeensuggestedthatthisprocesssuppliesformsofenergeticandanabolicsubstratesthatfavormassivemacromolecularsynthesis.

UnderstandingoftheWarburgeffect