Expression of anti-apoptotic factors modulates Apo2L/TRAIL resistance in colon carcinoma cells
- Mara S. LippaAffiliated withDepartment of Oncology, Amgen Inc.
- , Laura D. StrockbineAffiliated withDepartment of Oncology, Amgen Inc.
- , Tiep T. LeAffiliated withDepartment of Oncology, Amgen Inc.
- , Daniel G. BranstetterAffiliated withDepartment of Pathology, Amgen Inc.
- , Craig A. StrathdeeAffiliated withDepartment of Oncology, Amgen Inc.
- , Pamela M. HollandAffiliated withDepartment of Oncology, Amgen Inc. Email author
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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.
KeywordsApo2L/TRAIL XIAP shRNA Colorectal cancer Resistance Xenograft
- Expression of anti-apoptotic factors modulates Apo2L/TRAIL resistance in colon carcinoma cells
Volume 12, Issue 8 , pp 1465-1478
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- Kluwer Academic Publishers-Plenum Publishers
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- Colorectal cancer
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- Author Affiliations
- 1. Department of Oncology, Amgen Inc., 1201 Amgen Ct. West, Seattle, WA, 98119, USA
- 2. Department of Pathology, Amgen Inc., Seattle, WA, 98119, USA