Expression of anti-apoptotic factors modulates Apo2L/TRAIL resistance in colon carcinoma cells

Apoptosis. 2007 Aug;12(8):1465-78. doi: 10.1007/s10495-007-0076-6.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) selectively induces apoptosis in transformed cells. Normal cells and certain tumor cells can evade Apo2L/TRAIL induced cell death, but the determinants of Apo2L/TRAIL sensitivity are poorly understood. To better understand the factors that contribute to Apo2L/TRAIL resistance, we characterized two colon carcinoma lines with pronounced differences in Apo2L/TRAIL sensitivity. Colo205 cells are highly sensitive to Apo2L/TRAIL whereas Colo320 cells are unresponsive. Components of the DISC (death inducing signaling complex) could be immunoprecipitated from both cell lines in response to Apo2L/TRAIL. Sensitizing agents including a proteasome inhibitor conferred Apo2L/TRAIL sensitivity in Colo320 cells, indicating that the apoptotic machinery was intact and functional. We specifically suppressed the expression of Bcl-2, FLIP or XIAP in Colo320 cells. Downregulation of either FLIP or XIAP but not Bcl-2 restored sensitivity of Colo320 cells to Apo2L/TRAIL. Moreover, stable knockdown of XIAP expression in Colo320 subcutaneous tumors resulted in suppression of tumor growth and sensitivity to Apo2L/TRAIL in vivo. Our results indicate that only a specific subset of anti-apoptotic proteins can confer resistance to Apo2L/TRAIL in Colo320 cells. Elucidation of the factors that contribute to Apo2L/TRAIL resistance in tumor cells may provide insight into combination therapies with Apo2L/TRAIL in a clinical setting.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis Regulatory Proteins / genetics*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • Carcinoma / genetics*
  • Carcinoma / pathology
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / pathology
  • Death Domain Receptor Signaling Adaptor Proteins / metabolism
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • Mice
  • Mice, SCID
  • Receptors, Death Domain / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Tumor Cells, Cultured
  • X-Linked Inhibitor of Apoptosis Protein / genetics
  • Xenograft Model Antitumor Assays

Substances

  • Apoptosis Regulatory Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Death Domain Receptor Signaling Adaptor Proteins
  • Receptors, Death Domain
  • TNF-Related Apoptosis-Inducing Ligand
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human