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USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics
1Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Cell Death and Differentiation
|January 24, 2015
Summary
Inhibitor of apoptosis proteins (IAPs) are cancer targets. USP11 stabilizes cIAP2, conferring resistance to cancer therapies, but its inhibition sensitizes cells to apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Inhibitor of apoptosis proteins (IAPs) are key regulators of apoptosis and are targeted in cancer therapy.
- Resistance to Smac mimetics, a class of IAP-targeting drugs, is a significant clinical challenge.
Purpose of the Study:
- To investigate the mechanism of resistance to Smac mimetics in cancer cells.
- To identify novel regulators of cellular IAP2 (cIAP2) stability and their role in cancer therapy resistance.
Main Methods:
- Analysis of cIAP2 stability in cancer cell lines.
- Depletion studies of cIAP1 and cIAP2.
- Investigation of Ubiquitin-specific protease 11 (USP11) as a cIAP2 stabilizer.
- Assessment of USP11 expression in cancer tissues and correlation with survival.
- Evaluation of USP11 downregulation effects on apoptosis and tumor growth in vivo.
- Exploration of the TNFα/JNK pathway's role in USP11 expression and cIAP2 stability.
Main Results:
- Cellular IAP2 (cIAP2) is specifically stabilized in cancer cells, conferring resistance to Smac mimetics like BV6 and birinapant.
- Depletion of cIAP2, not cIAP1, sensitizes cancer cells to Smac mimetic-induced apoptosis.
- Ubiquitin-specific protease 11 (USP11) directly stabilizes cIAP2 and its overexpression correlates with poor survival in colorectal cancer and melanoma.
- High USP11 levels confer resistance to Smac mimetic-induced cIAP2 degradation, and USP11 downregulation sensitizes cells to apoptosis and inhibits tumor growth.
- The TNFα/JNK pathway upregulates USP11, maintaining cIAP2 stability and suggesting an alternative survival pathway.
Conclusions:
- USP11-mediated stabilization of cIAP2 represents a key mechanism of resistance to IAP-targeted cancer therapies.
- Targeting USP11 or disrupting the TNFα/JNK-USP11-cIAP2 axis could overcome therapeutic resistance.
- USP11 is a potential biomarker for predicting response to Smac mimetics and a therapeutic target in IAP-based cancer treatments.
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