MUC1c Regulates Cell Survival in Pancreatic Cancer by Preventing Lysosomal Permeabilization 英文参考文献.docVIP

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MUC1c Regulates Cell Survival in Pancreatic Cancer by Preventing Lysosomal Permeabilization 英文参考文献.doc

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MUC1c Regulates Cell Survival in Pancreatic Cancer by Preventing Lysosomal Permeabilization 英文参考文献

MUC1cRegulatesCellSurvivalinPancreaticCancerby PreventingLysosomalPermeabilization SulagnaBanerjee1,NameetaMujumdar1,VikasDudeja1,TiffanyMackenzie1,2,TaraK.Krosch1, VeenaSangwan1,SelwynM.Vickers1,3,AshokK.Saluja1,3 * 1Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota, United States of America, 2Department of Pharmacology,UniversityofMinnesota,Minneapolis,Minnesota,UnitedStatesofAmerica,3MasonicCancerCentre,UniversityofMinnesota,Minneapolis,Minnesota, UnitedStatesofAmerica Abstract Background: MUC1 is a type I transmembrane glycoprotein aberrantly overexpressed in various cancer cells including pancreaticcancer.ThecytosolicendofMUC1(MUC1-c)isextensivelyinvolvedinanumberofsignalingpathways.MUC1-cis reportedtoinhibitapoptosisinanumberofcancercells,butthemechanismofinhibitionisunclear. Method:ExpressionofMUC1-cwasstudiedinthepancreaticcancercelllineMIAPaCa-2attheRNAlevelbyusingqRTPCR and at the protein level by Western blotting. MUC1-c expression was inhibited either by siRNA or by a specific peptide inhibitor,GO-201.EffectofMUC1-cinhibitiononviabilityandproliferationandlysosomalpermeabilizationwerestudied. AssociationofMUC1-cwithHSP70wasdetectedbyco-immunoprecipitationofMUC1-candHSP70.LocalizationofMUC1-c in cellular organelles was monitored by immunofluorescence and with immuno- blotting by MUC1-c antibody after subcellularfractionation. Results:InhibitionofMUC1-cbyaninhibitor(GO-201)orsiRNAresultedinreducedviabilityandreducedproliferationof pancreaticcancercells.Furthermore,GO-201,thepeptideinhibitorofMUC1-c,waseffectiveinreducingtumorburdenin pancreaticcancermousemodel.MUC1-cwasalsofoundtobeassociatedwithHSP70inthecytosol,althoughasignificant amount of MUC1 was also seen to be present in the lysosomes. Inhibition of MUC1 expression or activity showed an enhanced Cathepsin B activity in the cytosol, indicating lysosomal permeabilization. Therefore this study indicates that MUC1-cinteractedwithHSP70i