Cell-wide metabolic alterations associated with malignancy PDF
Preview Cell-wide metabolic alterations associated with malignancy
METHODS IN ENZYMOLOGY Editors-in-Chief JOHN N. ABELSON and MELVIN I. SIMON Division of Biology California Institute of Technology Pasadena, California ANNA MARIE PYLE Departments of Molecular, Cellular and Developmental Biology and Department of Chemistry Investigator Howard Hughes Medical Institute Yale University Founding Editors SIDNEY P. COLOWICK and NATHAN O. KAPLAN AcademicPressisanimprintofElsevier 525BStreet,Suite1800,SanDiego,CA92101-4495,USA 225WymanStreet,Waltham,MA02451,USA Radarweg29,POBox211,1000AEAmsterdam,TheNetherlands TheBoulevard,LangfordLane,Kidlington,Oxford,OX51GB,UK 32JamestownRoad,LondonNW17BY,UK Firstedition2014 Copyright©2014,ElsevierInc.AllRightsReserved. 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Becauseofrapidadvancesinthemedicalsciences,inparticular,independentverificationof diagnosesanddrugdosagesshouldbemade ForinformationonallAcademicPresspublications visitourwebsiteatstore.elsevier.com ISBN:978-0-12-801329-8 ISSN:0076-6879 PrintedandboundinUnitedStatesofAmerica 14 15 16 17 11 10 9 8 7 6 5 4 3 2 1 CONTRIBUTORS ClaireAukim-Hastie FacultyofHealth&MedicalSciences,UniversityofSurrey,Guildford,andFacultyof Medicine,CancerSciencesandCESUnits,InstituteforLifeSciences,Universityof Southampton,Southampton,UnitedKingdom ChantalBauvy INSERMU1151-CNRSUMR8253,InstitutNeckerEnfants-Malades,UniversityParis Descartes,Pariscedex14,France MarisaBrini DepartmentofBiology,UniversityofPadova,Padova,Italy TitoCal`ı DepartmentofBiology,UniversityofPadova,Padova,Italy Jin-LianChen DepartmentofGastroenterology,ShanghaiEastHospital,TongjiUniversity,Schoolof Medicine,Shanghai,China AlexisChery MetabolomicsandCellBiologyPlatform,GustaveRoussy,andINSERM,U848, Villejuif,France ElisaCiraolo MolecularBiotechnologyCenter,DepartmentofMolecularBiotechnologyandHealth Sciences,UniversityofTorino,Torino,Italy PatriceCodogno INSERMU1151-CNRSUMR8253,InstitutNeckerEnfants-Malades,UniversityParis Descartes,Pariscedex14,France GuidoR.Y.DeMeyer LaboratoryofPhysiopharmacology,UniversityofAntwerp,Antwerp,Belgium DiegoDeStefani DepartmentofBiomedicalSciences,CNRNeuroscienceInstitute,UniversityofPadua, Padua,Italy NicolasDupont INSERMU1151-CNRSUMR8253,InstitutNeckerEnfants-Malades,UniversityParis Descartes,Pariscedex14,France SylvereDurand MetabolomicsandCellBiologyPlatform,GustaveRoussy,andINSERM,U848, Villejuif,France LorenzoGalluzzi Universite´ ParisDescartes/ParisV,SorbonneParisCite´;Equipe11labellise´eparlaLigue NationalecontreleCancer,CentredeRecherchedesCordeliers,Paris,andGustaveRoussy, Villejuif,France xi xii Contributors SheilaGanti DepartmentofComparativeMedicine,UniversityofWashington,Seattle,Washington,USA SpirosD.Garbis FacultyofMedicine,CancerSciencesandCESUnits,InstituteforLifeSciences,University ofSouthampton,Southampton,UnitedKingdom FedericoGulluni MolecularBiotechnologyCenter,DepartmentofMolecularBiotechnologyandHealth Sciences,UniversityofTorino,Torino,Italy YousangGwack DepartmentofPhysiology,DavidGeffenSchoolofMedicineatUCLA,LosAngeles, California,USA MarciaC.Haigis DepartmentofCellBiology,HarvardMedicalSchool,Boston,Massachusetts,USA JuliaM.Hill DepartmentofCellandDevelopmentalBiology,ConsortiumforMitochondrialResearch, UniversityCollegeLondon,London,UnitedKingdom EmilioHirsch MolecularBiotechnologyCenter,DepartmentofMolecularBiotechnologyandHealth Sciences,UniversityofTorino,Torino,Italy AlfredoJ.Iba´n˜ez DepartmentofChemistryandAppliedBiosciences,Eidgeno€ssicheTechnischeHochschule Zurich,Zurich,Switzerland Li-JuanJi DepartmentofRehabilitation,TheSecondPeople’sHospitalofHuai’an,Huai’an,China AleckW.E.Jones DepartmentofCellandDevelopmentalBiology,ConsortiumforMitochondrialResearch, UniversityCollegeLondon,London,UnitedKingdom StefanKempa BerlinInstituteforMedicalSystemsBiologyattheMDCBerlin-Buch,Berlin,Germany HectorKeun DepartmentofSurgeryandCancer,ImperialCollegeLondon,SouthKensington,London, UnitedKingdom Kyun-DoKim DepartmentofPhysiology,DavidGeffenSchoolofMedicineatUCLA,LosAngeles, California,USA ImhoiKoo DepartmentofChemistry,UniversityofLouisville,Louisville,Kentucky,USA GuidoKroemer MetabolomicsandCellBiologyPlatform,GustaveRoussy;INSERM,U848;Villejuif, France;Universite´ParisDescartes/ParisV,SorbonneParisCite´;Equipe11labellise´eparla Contributors xiii LigueNationalecontreleCancer,CentredeRecherchedesCordeliers,andPoˆlede Biologie,HoˆpitalEurope´enGeorgesPompidou,AP-HP,Paris,France XiaojieLu DepartmentofGastroenterology,ShanghaiEastHospital,TongjiUniversity,Schoolof Medicine,Shanghai,China WimMartinet LaboratoryofPhysiopharmacology,UniversityofAntwerp,Antwerp,Belgium IdilOrhon INSERMU1151-CNRSUMR8253,InstitutNeckerEnfants-Malades,UniversityParis Descartes,Pariscedex14,France DenisOttolini DepartmentofBiology,UniversityofPadova,Padova,Italy MatthiasPietzke BerlinInstituteforMedicalSystemsBiologyattheMDCBerlin-Buch,Berlin,Germany JuanRamonHernandez-Fernaud VascularProteomicsGroup,CancerResearchUKBeatsonInstitute,Glasgow, UnitedKingdom StevenReid VascularProteomicsGroup,CancerResearchUKBeatsonInstitute,Glasgow, UnitedKingdom RosarioRizzuto DepartmentofBiomedicalSciences,CNRNeuroscienceInstitute,UniversityofPadua, Padua,Italy AsierRuiz DepartmentofNeurosciences,UniversityoftheBasqueCountry(UPV/EHU),Achu´carro BasqueCenterforNeuroscience-UPV/EHU,Leioa,Spain;InstitutodeSaludCarlosIII, CentrodeInvestigacio´nBiome´dicaenReddeEnfermedadesNeurodegenerativas, (CIBERNED),Madrid,Spain F.KyleSatterstrom HarvardSchoolofEngineeringandAppliedSciences,Cambridge,andDepartmentofCell Biology,HarvardMedicalSchool,Boston,Massachusetts,USA MarieScoazec MetabolomicsandCellBiologyPlatform,GustaveRoussy,andINSERM,U848,Villejuif, France SonalSrikanth DepartmentofPhysiology,DavidGeffenSchoolofMedicineatUCLA,LosAngeles, California,USA AlesˇSvatosˇ MassSpectrometry/ProteomicResearchGroup,MaxPlanckinstitute,Jena,Germany xiv Contributors GyorgySzabadkai DepartmentofCellandDevelopmentalBiology,ConsortiumforMitochondrialResearch, UniversityCollegeLondon,London,UnitedKingdom,andDepartmentofBiomedical Sciences,CNRNeuroscienceInstitute,UniversityofPadua,Padua,Italy Jean-PierreTimmermans LaboratoryofCellBiologyandHistology,UniversityofAntwerp,Antwerp,Belgium XiaoliWei DepartmentofChemistry,UniversityofLouisville,Louisville,Kentucky,USA RobertH.Weiss DivisionofNephrology,DepartmentofInternalMedicine,UniversityofCalifornia,Davis, andMedicalService,SacramentoVAMedicalCenter,Sacramento,California,USA HiromiI.Wettersten DivisionofNephrology,DepartmentofInternalMedicine,UniversityofCalifornia,Davis, California,USA SaraZanivan VascularProteomicsGroup,CancerResearchUKBeatsonInstitute,Glasgow,United Kingdom XiangZhang DepartmentofChemistry,UniversityofLouisville,Louisville,Kentucky,USA PREFACE: ONCOMETABOLISM: A NEW FIELD OF RESEARCH WITH PROFOUND THERAPEUTIC IMPLICATIONS In 1924, the German physiologist Otto Heinrich Warburg was the first to reportthepropensityofneoplasticcellstometabolizeglucoseviaaerobicgly- colysisratherthanviathecitricacidcycle(alsoknownasKrebscycle)asafuel for mitochondrialrespiration(Koppenol,Bounds, & Dang, 2011;Warburg, 1924).Foralongtimesincethen,however,muchgreaterattentionhasbeen attracted by the discovery of the genetic and epigenetic alterations that characterize cancer cells than by their metabolic profile. Such a tendency wassopronouncedthat,attheendofthetwentiethcentury,severalchemo- therapeutic agents specifically targeting oncogeneaddiction,i.e.,theprocess whereby cancer cells rely for their survival and growth on the constitutive activationofoncogenicsignalingpathwaysand/oronthepermanentinacti- vation of oncosuppressive mechanisms, were licensed for use in cancer patients(Luo,Solimini,&Elledge,2009,).Conversely,nochemotherapeutic agentspecificallydevisedtotargetthemetabolismofcancercellswasavailable then,noritisnow,although(1)severalwidelyemployedandeffectiveche- motherapeutics including methotrexate, 5-fluorouracil, gemcitabine, and manyothers(whicharecumulativelyknownasantimetabolites),defactoexert antineoplastic effects by operating as metabolic inhibitors (but were discov- eredanddevelopedbasedonempirical,asopposedtomechanistic,grounds); and (2) the safety and therapeutic profile of many of these agents are being evaluated in a growing number of clinical trials (Chabner & Roberts, 2005;Galluzzi,Kepp,VanderHeiden,&Kroemer,2013).Indeed,itisonly overthepastdecadethatthecomplexityandprominenttherapeuticimplica- tionsofoncometabolism,whichcanbedefinedastheensembleofmetabolic rearrangements that accompany oncogenesis and tumor progression, have been fully recognized as a central aspect of malignant transformation (Hanahan & Weinberg, 2011). As a result of such a refocus in the interest of researchers and clinicians, the metabolic rewiring of cancer cells is now viewed as a rich source of targets for the development of novel chemother- apeutic agents, and an intense wave of investigation currently explores this possibility (Galluzzi et al., 2013; Vander Heiden, 2011). At odds with long-standing beliefs, it is now clear that the so-called Warburgeffectrepresentsonlythetipoftheicebergofmetabolicalterations xv xvi Preface associated with oncogenesis, which also encompass an increased flux throughthepentosephosphatepathway,elevatedratesoflipidbiosynthesis, intenseglutamineconsumption,animprovedcontrolofredoxhomeostasis, and(atleastintheinitialstepsofmalignanttransformation)decreasedlevels of macroautophagy (Schulze & Harris, 2012; Vander Heiden, Cantley, & Thompson, 2009; White, 2012). A few other common misconceptions about oncometabolism are in the process of being reconsidered based on preclinical and clinical findings from several laboratories worldwide. First,themetabolicrewiringofneoplasticcellsshouldnotbeconsidered as aself-standing hallmarkof malignancy, but ratheras a phenomenonthat intimatelyaccompanies,allowsforandcannotbemechanisticallyseparated frommany,ifnotall,aspectsofoncogenesis(Galluzzietal.,2013;Locasale& Cantley, 2011; Wellen& Thompson, 2012). Accumulating evidence indi- cates indeed that (1) several metabolic intermediates such as ATP, acetyl-CoA,a-ketoglutarate, andreactiveoxygenspeciesplayamajorrole in cell-intrinsic as well as cell-extrinsic signaling pathways (Galluzzi, Kepp, & Kroemer, 2012; Locasale & Cantley, 2011; Wellen & Thompson, 2012); (2) multiple proteins with prominent metabolic func- tionssuchascytochromec(whichoperatesasanelectronshuttleinthemito- chondrialrespiratorychain)andtheM2isoformofpyruvatekinase(PKM2, which catalyzes the last step glycolysis) participate in signal transduction (Galluzzi, Kepp, & Kroemer, 2012; Galluzzi, Kepp, Trojel-Hansen, & Kroemer, 2012; Gao, Wang, Yang, Liu, & Liu, 2012; Luo et al., 2011; Yangetal., 2011);and(3)severalproteinsinitiallyviewedas“pure”signal transducers including (but not limited to) the antiapoptotic Bcl-2 family members BCL-X and MCL1 also impact on metabolic functions such as L the handling of Ca2+ ions at the endoplasmic reticulum and the enzymatic activity of the F F ATP synthase (Alavian et al., 2011; Perciavalle et al., 1 0 2012; Rong & Distelhorst, 2008). Second, the metabolic changes linked to malignant transformation shouldnotbeconsideredasageneralpropertysharedbyalltypesofcancer. Ithasindeedbeenclearlydemonstratedthatseveralvariablesincludingtissue type and oncogenic driver (and presumably many others) determine the metabolicprofileofdevelopingtumors(Yunevaetal.,2012).Thishasobvi- ous implications for the use of metabolic inhibitors in cancer therapy. Third,itshouldbekeptinmindthatthemetabolicprofileofneoplastic cellsisfarlessspecificthanpreviouslythought,but(withsomeexceptions) resemblethatofhighlyproliferatingnontransformedcells(Altman&Dang, 2012;Michalek&Rathmell,2010).Thisnotioniscorroboratedbythefact Preface xvii that the most severe side effects of antimetabolites involve highly prolifer- ating normal tissues, such as the intestinal epithelium and bone marrow (Chabner & Roberts, 2005,). Nonetheless, the clinical success of these widelyemployedchemotherapeuticagentspointstotheexistenceofather- apeutic window for the use of metabolic inhibitors in cancer patients (Galluzzi et al., 2013; Vander Heiden, 2011). As it stands, multiple facets of oncometabolism can be considered as forms of “nononcogene addiction,” a term referring to the fact that the survival of malignant cells relies not only on the constitutive activation of oncogenes and/or the per- manentinactivationofoncosuppressivemechanismsbutalsoonawidearray ofgenesandfunctionsthatarenotinherentlytumorigenic(Luoetal.,2009). Finally, tumors (in particular solid neoplasms but also hematological malignancies) should no longer be considered as homogenous entities pre- dominantly composed of malignant cells. Indeed, it is now clear that neo- plastic lesions contain a large amount of nontransformed cells, including endothelial, stromal, and immune cells, and that oncogenesis takes place in the context of a complex network of physical and functional interactions amongthemalignantandnonmalignantcomponentsofthetumormicroen- vironment (Nagaraj & Gabrilovich, 2010; Pietras & Ostman, 2010). These interactions, part of which have direct metabolic implications (Nieman etal.,2011;Sonveaux et al., 2008; Whitaker-Menezesetal., 2011), are also attracting attention as targets for the development of novel antineoplastic agents (Galluzzi, Senovilla, Zitvogel, & Kroemer, 2012; Zitvogel, Galluzzi, Smyth, & Kroemer,2013). In OncoMetabolism, a thematic collection covering two volumes of the successful Methods in Enzymology series, leading researchers summarize the currentstateofthefieldfrombothaconceptualandmethodologicalstand- point.Thefirstvolume,entitled“Conceptualbackgroundandbioenergetic/mito- chondrialaspectsofoncometabolism,”providesarobusttheoreticalbackground on cancer-associated metabolic alterations, discussing how these relate to otheraspectsofoncogenesissuchastherelentlessproliferationandresistance to death exhibited by neoplastic cells. Thereafter, this volume offers a col- lectionoftechniquesthatcanbeemployedtostudythemajorbioenergetic andmitochondrialaspectsofoncometabolism,including(butnotlimitedto) alterationsinglycolysisandoxidativephosphorylation.Thesecondvolume, entitled “Cell-wide metabolic alterations associated with malignancy,” proposes a series of methods for the investigation of global facets of oncometabolism, including (but not limited to) deregulations in Ca2+ fluxes and autophagy, as well as (malignant) cell- or tissue-wide metabolomic alterations. xviii Preface OncoMetabolismis expectedto provideacomprehensiveandreliable meth- odologicalguidetobeginnersandexpertsinthisexcitingandrapidlyexpan- ding area of cancer research. ACKNOWLEDGMENTS LorenzoGalluzziandGuidoKroemeraresupportedbytheLiguecontreleCancer(e´quipe labellise´e),AgenceNationaldelaRecherche(ANR),AXAChairforLongevityResearch, ARC, Cance´ropoˆle Ile-de-France, Institut National du Cancer (INCa), Fondation Bettencourt-Schueller, Fondation de France, Fondation pour la Recherche Me´dicale (FRM), the European Commission (ArtForce), the European Research Council (ERC), the LabEx Immuno-Oncology, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), the SIRIC Cancer Research and Personalized Medicine (CARPEM), and the Paris Alliance of Cancer Research Institutes(PACRI). REFERENCES Alavian,K.N.,Li,H.,Collis,L.,Bonanni,L.,Zeng,L.,Sacchetti,S.,etal.(2011).Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FOATPsynthase.NatureCellBiology,13,1224–1233. Altman,B.J.,&Dang,C.V.(2012).Normalandcancercellmetabolism:Lymphocytesand lymphoma.TheFEBSJournal,279,2598–2609. 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