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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.
Abstract:
Given their crucial role in apoptosis suppression, inhibitor of apoptosis proteins (IAPs) have recently become attractive targets for cancer therapy. Here, we report that cellular IAP2 (cIAP2) is specifically stabilized in several cancer cell lines, leading to resistance to Smac mimetics, such as BV6 and birinapant. In particular, our results showed that cIAP2 depletion, but not cIAP1 depletion, sensitized cancer cells to Smac mimetic-induced apoptosis. Ubiquitin-specific protease 11 (USP11) is a deubiquitylase that directly stabilizes cIAP2. USP11 overexpression is frequently found in colorectal cancer and melanoma and is correlated with poor survival. In our study, cancer cell lines expressing high levels of USP11 exhibited strong resistance to Smac mimetic-induced cIAP2 degradation. Furthermore, USP11 downregulation sensitized these cells to apoptosis induced by TRAIL and BV6 and suppressed tumor growth in a xenograft model. Finally, the TNFα/JNK pathway induced USP11 expression and maintained cIAP2 stability, suggesting an alternative TNFα-dependent cell survival pathway. Collectively, our data suggest that USP11-stabilized cIAP2 may serve as a barrier against IAP-targeted clinical approaches.
Insights
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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