Apoptosis

, Volume 12, Issue 8, pp 1465–1478 | Cite as

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

  • Mara S. Lippa
  • Laura D. Strockbine
  • Tiep T. Le
  • Daniel G. Branstetter
  • Craig A. Strathdee
  • Pamela M. Holland
Original Paper

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.

Keywords

Apo2L/TRAIL XIAP shRNA Colorectal cancer Resistance Xenograft 

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Mara S. Lippa
    • 1
  • Laura D. Strockbine
    • 1
  • Tiep T. Le
    • 1
  • Daniel G. Branstetter
    • 2
  • Craig A. Strathdee
    • 1
  • Pamela M. Holland
    • 1
  1. 1.Department of OncologyAmgen Inc.SeattleUSA
  2. 2.Department of PathologyAmgen Inc.SeattleUSA

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