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

J Am Coll Surg. 2004 Jun;198(6):953-9. doi: 10.1016/j.jamcollsurg.2004.01.037.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Antimetabolites, Antineoplastic / pharmacology*
  • Apoptosis
  • Blotting, Western
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology*
  • Drug Resistance, Neoplasm
  • Humans
  • Pancreatic Neoplasms / drug therapy*
  • RNA, Small Interfering / pharmacology*
  • Tumor Cells, Cultured
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / physiology*

Substances

  • Antimetabolites, Antineoplastic
  • RNA, Small Interfering
  • Deoxycytidine
  • gemcitabine
  • src-Family Kinases