Alterations in Cellular Energy Metabolism Associated with the Antiproliferative Effects of the ATM Inhibitor KU-55933 and with Metformin 英文参考文献.docVIP

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Alterations in Cellular Energy Metabolism Associated with the Antiproliferative Effects of the ATM Inhibitor KU-55933 and with Metformin 英文参考文献.doc

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Alterations in Cellular Energy Metabolism Associated with the Antiproliferative Effects of the ATM Inhibitor KU-55933 and with Metformin 英文参考文献

AlterationsinCellularEnergyMetabolismAssociated withtheAntiproliferativeEffectsoftheATMInhibitor KU-55933andwithMetformin MahvashZakikhani1,2,MiguelBazile2,SinaHashemi2,ShivaJaveshghani4,DainaAvizonis3 ,Julie StPierre3,5,MichaelN.Pollak1,2,3,4 * 1Department of Oncology, McGill University, Montreal, Quebec, Canada, 2Division of Cancer Prevention, McGill University, Montreal, Quebec, Canada, 3Goodman CancerResearchCentre,McGillUniversity,Montreal,Quebec,Canada,4DivisionofExperimentalMedicine,McGillUniversity,Montreal,Quebec,Canada,5Departmentof Biochemistry,McGillUniversity,Montreal,Quebec,Canada Abstract KU-55933 is a specific inhibitor of the kinase activity of the protein encoded by Ataxia telangiectasia mutated (ATM), an importanttumorsuppressorgenewithkeyrolesinDNArepair.Unexpectedlyforaninhibitorofatumorsuppressorgene, KU-55933reducesproliferation.Inviewofpriorpreliminaryevidencesuggestingdefectivemitochondrialfunctionincellsof patientswithAtaxiaTelangiectasia(AT),weexaminedenergymetabolismofcellstreatedwithKU-55933.Thecompound increasedAMPKactivation,glucoseuptakeandlactateproductionwhilereducingmitochondrialmembranepotentialand coupledrespiration.ThestimulationofglycolysisbyKU-55933didnotfullycompensateforthereductioninmitochondrial functions,leadingtodecreasedcellularATPlevelsandenergystress.Theseactionsaresimilartothosepreviouslydescribed forthebiguanidemetformin,apartialinhibitorofrespiratorycomplexI.Bothcompoundsdecreasedmitochondrialcoupled respirationandreducedcellularconcentrationsoffumarate,malate,citrate,andalpha-ketogluterate.Succinatelevelswere increasedbyKU-55933levelsanddecreasedbymetformin,indicatingthattheeffectsofATMinhibitionandmetforminare not identical. These observations suggest a role for ATM in mitochondrial function and show that both KU-55933 and metforminperturbtheTCAcycleaswellasoxidativephosphorylation. Citation:ZakikhaniM,BazileM,HashemiS,JaveshghaniS,AvizonisD,etal.(2012)AlterationsinCellularEnergyMetabolismAssociatedwiththeAntip