Rapamycin Response in Tumorigenic and Non-Tumorigenic Hepatic Cell Lines 英文参考文献.docVIP

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Rapamycin Response in Tumorigenic and Non-Tumorigenic Hepatic Cell Lines 英文参考文献.doc

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Rapamycin Response in Tumorigenic and Non-Tumorigenic Hepatic Cell Lines 英文参考文献

RapamycinResponseinTumorigenicandNon- TumorigenicHepaticCellLines RosaH.Jimenez1.,JoanM.Boylan1.,Ju-SeogLee2,MirkoFrancesconi3,GastoneCastellani3,JenniferA. Sanders1,PhilipA.Gruppuso1* 1DepartmentofPediatrics,RhodeIslandHospitalandBrownUniversity,Providence,RhodeIsland,UnitedStatesofAmerica,2DepartmentofSystemsBiology,Divisionof Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America, 3Interdepartmental Center ‘‘L. Galvani,’’ University of Bologna,Bologna,Italy Abstract Background: The mTOR inhibitor rapamycin has anti-tumor activity across a variety of human cancers, including hepatocellularcarcinoma.However,resistancetoitsgrowthinhibitoryeffectsiscommon.Wehypothesizedthathepaticcell lineswithvaryingrapamycinresponsivenesswouldshowcommoncharacteristicsaccountingforresistancetothedrug. Methodology/Principal Findings: We profiled a total of 13 cell lines for rapamycin-induced growth inhibition. The non- tumorigenic rat liver epithelial cell line WB-F344 was highly sensitive while the tumorigenic WB311 cell line, originally derivedfromtheWB-F344line,washighlyresistant.Theother11celllinesshowedawiderangeofsensitivities.Rapamycin inducedinhibitionofcyclinE–dependentkinaseactivityinsomecelllines,buttheabilitytodosodidnotcorrelatewith sensitivity.InhibitionofcyclinE–dependentkinaseactivitywasrelatedtoincorporationofp27Kip1intocyclinE–containing complexesinsomebutnotallcelllines.Similarly,sensitivityofglobalproteinsynthesistorapamycindidnotcorrelatewith itsanti-proliferativeeffect.However,rapamycinpotentlyinhibitedphosphorylationoftwokeysubstrates,ribosomalprotein S6 and 4E-BP1, in all cases, indicating that the locus of rapamycin resistance was downstream from inhibition of mTOR Complex 1. Microarray analysis did not disclose a unifying mechanism for rapamycin resistance, although the glycolytic pathwaywasdownregulatedinallfourcelllinesstudied. Conclusions/Significance:Weconcludethatthemechanismsofrapamycinresistanceinh