SKP2 confers resistance of pancreatic cancer cells towards TRAIL-induced apoptosis

Int J Oncol. 2011 Jan;38(1):219-25.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dismal prognosis and no effective conservative therapy exists. Although the F-box protein S-phase kinase associated protein 2 (SKP2) is highly expressed and regulates cell cycle progression in PDAC, alternative SKP2 functions in PDAC are unknown. Using RNA interference we now demonstrate that SKP2 confers resistance of a subset of PDAC cell lines towards the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), but not the topoisomerase II inhibitor etoposide. We observed accelerated cleavage of the BH3-only protein Bid and augmented downregulation of cFLIPL, XIAP and MCL1 upon treatment of SKP2-depleted MiaPaCa2 cells with TRAIL. Our data disclose a novel SKP2 function in PDAC cells and therefore define SKP2 as a molecular target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Humans
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • S-Phase Kinase-Associated Proteins / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Transfection
  • Tumor Cells, Cultured

Substances

  • S-Phase Kinase-Associated Proteins
  • TNF-Related Apoptosis-Inducing Ligand