Altering Chemosensitivity by Modulating Translation Elongation 英文参考文献.docVIP

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Altering Chemosensitivity by Modulating Translation Elongation 英文参考文献.doc

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Altering Chemosensitivity by Modulating Translation Elongation 英文参考文献

AlteringChemosensitivitybyModulatingTranslation Elongation FrancisRobert1,MarilynCarrier1,SveaRawe1,SamuelChen1,ScottLowe2,JerryPelletier1,3* 1DepartmentofBiochemistry,McGillUniversity,Montreal,Quebec,Canada,2HowardHughesMedicalInstitute,ColdSpringHarborLaboratory,ColdSpringHarbor,New York,UnitedStatesofAmerica,3McGillCancerCenter,McGillUniversity,Montreal,Quebec,Canada Abstract Background: The process of translation occurs at a nexus point downstream of a number of signal pathways and developmentalprocesses.ModelingactivationofthePTEN/AKT/mTORpathwayintheEm-Mycmouseisavaluabletoolto studytumorgenotype/chemosensitivityrelationshipsinvivo.Inthismodel,blockingtranslationinitiationwithsilvestrol,an inhibitor of the ribosome recruitment step has been showed to modulate the sensitivity of the tumors to the effect of standardchemotherapy.However,inhibitorsoftranslationelongationhavebeentestedaspotentialanti-cancertherapeutic agents in vitro, but have not been extensively tested in genetically well-defined mouse tumor models or for potential synergywithstandardofcareagents. Methodology/PrincipalFindings:Here,wechosefourstructurallydifferentchemicalinhibitorsoftranslationelongation: homoharringtonine,bruceantin,didemninBandcycloheximide,andtestedtheirabilitytoalterthechemoresistanceofEm- myc lymphomas harbouring lesions in Pten, Tsc2, Bcl-2, or eIF4E. We show that in some genetic settings, translation elongation inhibitors are able to synergize with doxorubicin by reinstating an apoptotic program in tumor cells. We attributethiseffecttoareductioninlevelsofpro-oncogenicorpro-survivalproteinshavingshorthalf-lives,likeMcl-1,cyclin D1orc-Myc.Usinglymphomascellsgrownexvivowereproducedthesynergyobservedinmicebetweenchemotherapy andelongationinhibitionandshowthatthisisreversedbyblockingproteindegradationwithaproteasomeinhibitor. Conclusion/Significance: Our results indicate that depleting short-lived pro-survival factors by inhibiting their synthesis couldachieveatherapeuticresp