Targeted silencing of TRPM7 ion channel induces replicative senescence and produces enhanced cytotoxicity with gemcitabine in pancreatic adenocarcinoma

Cancer Lett. 2012 May 1;318(1):99-105. doi: 10.1016/j.canlet.2011.12.007. Epub 2011 Dec 11.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Antimetabolites, Antineoplastic / pharmacology*
  • Apoptosis
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation
  • Cellular Senescence*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Exodeoxyribonucleases / genetics
  • Exodeoxyribonucleases / metabolism
  • Humans
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • RNA Interference*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • RecQ Helicases / genetics
  • RecQ Helicases / metabolism
  • Werner Syndrome Helicase

Substances

  • Antimetabolites, Antineoplastic
  • CDKN1B protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • RNA, Messenger
  • RNA, Small Interfering
  • Deoxycytidine
  • Cyclin-Dependent Kinase Inhibitor p27
  • gemcitabine
  • Exodeoxyribonucleases
  • RecQ Helicases
  • WRN protein, human
  • Werner Syndrome Helicase