Oxygen Consumption Can Regulate the Growth of Tumors, a New Perspective on the Warburg Effect 英文参考文献.docVIP

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Oxygen Consumption Can Regulate the Growth of Tumors, a New Perspective on the Warburg Effect 英文参考文献.doc

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Oxygen Consumption Can Regulate the Growth of Tumors, a New Perspective on the Warburg Effect 英文参考文献

OxygenConsumptionCanRegulatetheGrowthof Tumors,aNewPerspectiveontheWarburgEffect YijunChen1,2,RobCairns1,IoannaPapandreou1,AlbertKoong1.,NicholasC.Denko1. * 1DivisionofRadiationandCancerBiology,DepartmentofRadiationOncology,StanfordUniversitySchoolofMedicine,Stanford,California,UnitedStatesofAmerica, 2DepartmentofSurgery,StanfordUniversitySchoolofMedicine,Stanford,California,UnitedStatesofAmerica Abstract Background:TheuniquemetabolismoftumorswasdescribedmanyyearsagobyOttoWarburg,whoidentifiedtumorcells with increased glycolysis and decreased mitochondrial activity. However, ‘‘aerobic glycolysis’’ generates fewer ATP per glucose molecule than mitochondrial oxidative phosphorylation, so in terms of energy production, it is unclear how increasingalessefficientprocessprovidestumorswithagrowthadvantage. Methods/Findings: We carried out a screen for loss of genetic elements in pancreatic tumor cells that accelerated their growth as tumors, and identified mitochondrial ribosomal protein L28 (MRPL28). Knockdown of MRPL28 in these cells decreasedmitochondrialactivity,andincreasedglycolysis,butparadoxically,decreasedcellulargrowthinvitro.Following Warburg’sobservations,thismutationcausesdecreasedmitochondrialfunction,compensatoryincreaseinglycolysisand acceleratedgrowthinvivo.Likewise,knockdownofeithermitochondrialribosomalproteinL12(MRPL12)orcytochrome oxidase had a similar effect. Conversely, expression of the mitochondrial uncoupling protein 1 (UCP1) increased oxygen consumption and decreased tumor growth. Finally, treatment of tumor bearing animals with dichloroacetate (DCA) increasedpyruvateconsumptioninthemitochondria,increasedtotaloxygenconsumption,increasedtumorhypoxiaand slowedtumorgrowth. Conclusions:Weinterpretthesefindingstoshowthatnon-oncogenicgeneticchangesthataltermitochondrialmetabolism can regulate tumor growth through modulation of the consumption of oxygen, which appears to be a rate limiting substratefortumorproliferation. Citation: Chen Y, Cairns R, Pa