title: Targeted silencing of TRPM7 ion channel induces replicative senescence and produces enhanced cytotoxicity with gemcitabine in pancreatic adenocarcinoma.
abstract: The transient receptor potential TRPM7 ion channel is required for cellular proliferation in pancreatic epithelia and adenocarcinoma. To elucidate the mechanism that mediates the function of TRPM7, we examined its role in survival of pancreatic cancer cells. RNA interference-mediated silencing of TRPM7 did not induce apoptotic cell death. TRPM7-deficient cells underwent replicative senescence with up-regulation of p16(CDKN2A) and WRN mRNA. The combination of anti-TRPM7 siRNA and gemcitabine produced enhanced cytotoxicity as compared to gemcitabine alone. Thus, TRPM7 is required for preventing senescence, and modulation of TRPM7 expression may help improve treatment response of pancreatic cancer by combining with apoptosis-inducing agents.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Penn State College of Medicine, Pennsylvania State University, 500 University Drive, Hershey, PA 17033, USA. nyee@hmc.psu.edu
authors.forename: Nelson S
authors.initials: NS
authors.lastname: Yee
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhou
authors.forename: Minsun
authors.initials: M
authors.lastname: Lee
authors.forename: Rosemary K
authors.initials: RK
authors.lastname: Yee
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism; D000071657:Werner Syndrome Helicase; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C436291:CDKN1B protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D003841:Deoxycytidine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D000093542:Gemcitabine