RNA interference targeting focal adhesion kinase enhances pancreatic adenocarcinoma gemcitabine chemosensitivity

Biochem Biophys Res Commun. 2003 Nov 21;311(3):786-92. doi: 10.1016/j.bbrc.2003.10.060.

Abstract

Focal adhesion kinase (FAK) is an important regulator of cellular signaling, migration, apoptosis, and cell cycle progression. We tested the hypothesis that FAK is a determinant of gemcitabine chemoresistance in pancreatic adenocarcinoma cells and examined the effect of inhibiting FAK expression on gemcitabine-induced cytotoxicity in vitro and in vivo. FAK expression was quantified by Western and Northern blots. Expression of FAK was suppressed using small interfering RNA (siRNA). Gemcitabine-induced cytotoxicity was quantified and apoptosis was characterized. Akt activity was determined by in vitro kinase assay. We assessed the therapeutic applicability of FAK siRNA in a nude mouse orthotopic xenograft model. While not affecting cellular proliferation or apoptosis in the absence of gemcitabine, FAK siRNA potentiated gemcitabine-induced cytotoxicity in vitro and in vivo. FAK siRNA treatment suppressed Akt activity, which may contribute to its chemosensitizing effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Animals
  • Apoptosis
  • Blotting, Northern
  • Blotting, Western
  • Caspases / metabolism
  • Cell Line, Tumor
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Pancreas / metabolism
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Protein-Serine-Threonine Kinases*
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA / metabolism
  • RNA Interference*
  • RNA, Small Interfering / metabolism
  • Transfection

Substances

  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Deoxycytidine
  • RNA
  • gemcitabine
  • Protein-Tyrosine Kinases
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • PTK2 protein, human
  • Ptk2 protein, mouse
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Caspases