siRNA directed against c-Src enhances pancreatic adenocarcinoma cell gemcitabine chemosensitivity

Mark S. Duxbury, Hiromichi Ito, Michael J. Zinner, Stanley W. Ashley, Edward E. Whang

Research output: Contribution to journalArticlepeer-review

Abstract

Background The c-Src tyrosine kinase is a determinant of malignant cellular behavior in a variety of human cancers. We sought to determine the effect of suppressing c-Src expression on pancreatic adenocarcinoma chemosensitivity to gemcitabine. Study design PANC1, MIAPaCa2, BxPC3, and Capan2 pancreatic adenocarcinoma cell lines were studied. Expression of c-Src was determined by Western blot analysis. c-Src kinase activity was determined by in vitro kinase assay. RNA interference was used to suppress c-Src expression. Gemcitabine-induced cytotoxicity was determined by tetrazolium reduction assay and caspase profiling was performed. The effect of Src-specific siRNA on Akt activity was quantified. Results Src expression and kinase activity in cell lines were directly correlated with gemcitabine chemoresistance. c-Src-specific siRNA suppressed c-Src expression and kinase activity. c-Src-specific siRNA increased gemcitabine-induced, caspase-mediated apoptosis. Akt activity was decreased by suppression of c-Src expression. Conclusions c-Src is a determinant of pancreatic adenocarcinoma chemoresistance and represents a potential target for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)953-959
Number of pages7
JournalJournal of the American College of Surgeons
Volume198
Issue number6
DOIs
StatePublished - Jun 2004

Keywords

  • 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide
  • GSK-3
  • IC
  • MTT
  • concentration required to inhibit proliferation by 50%
  • glycogen synthase kinase-3
  • siRNA
  • small interfering RNA

ASJC Scopus subject areas

  • Surgery

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