Neuregulin Promotes Incomplete Autophagy of Prostate Cancer Cells That Is Independent of mTOR Pathway Inhibition 英文参考文献.docVIP

NeuregulinPromotesIncompleteAutophagyofProstate CancerCellsThatIsIndependentofmTORPathway Inhibition EranSchmukler1,BenShai2,MarceloEhrlich2,RonitPinkas-Kramarski1* 1DepartmentofNeurobiology,Tel-AvivUniversity,Ramat-Aviv,Israel,2DepartmentofCellResearchandImmunology,Tel-AvivUniversity,Ramat-Aviv,Israel Abstract Background: Growth factors activating the ErbB receptors have been described in prostate tumors. The androgen dependentprostatecancercellline,LNCaP,expressestheErbB-1,ErbB-2andErbB-3receptortyrosinekinases.Previously,it wasdemonstratedthatNRGactivatesErbB-2/ErbB-3heterodimerstoinduceLNCaPcelldeath,whereas,EGFactivatesErbB- 1/ErbB-1orErbB-1/ErbB-2dimerstoinducecellgrowthandsurvival.ItwasalsodemonstratedthatPI3Kinhibitorsrepressed thiscelldeathsuggestingthatinandrogendeprivedLNCaPcells,NRGactivatesaPI3K-dependentpathwayassociatedwith celldeath. Methodology/PrincipalFindings:InthepresentstudywedemonstratethatNRGinducesautophagyinLNCaPcells,using LC3 as a marker. However, the autophagy induced by NRG may be incomplete since p62 levels elevate. We also demonstrated that NRG- induced autophagy is independent of mammalian target of rapamycin (mTOR) inhibition since NRGinducesAktandS6K activation.Interestingly, inhibitionofreactiveoxygenspecies (ROS)by N-acetylcysteine(NAC), inhibitedNRG-inducedautophagyandcelldeath.OurstudyalsoidentifiedJNKandBeclin1asimportantcomponentsin NRG-induced autophagy and cell death. NRG induced elevation in JNK phosphorylation that was inhibited by NAC. Moreover, inhibitor of JNK inhibited NRG-induced autophagy and cell death. Also, in cells overexpressing Bcl-2 or cells expressingsh-RNAagainstBeclin1,theeffectsofNRG,namelyinductionofautophagyandcelldeath,wereinhibited. Conclusions/Significance: Thus, in LNCaP cells, NRG-induces incomplete autophagy and cell death that depend on ROS levels.TheseeffectsofNRGaremediatedbysignalingpathwaythatactivatesJNKandBeclin1,butisindependentofmTOR inhibition. Citation:SchmuklerE,ShaiB,EhrlichM,Pi