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.
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Abbreviations
- IAP:
-
inhibitor of apoptosis
- cIAP2:
-
cellular IAP2
- BIR:
-
baculoviral IAP repeat
- XIAP:
-
X chromosome-linked IAP
- ML-IAP:
-
melanoma IAP
- USP11:
-
ubiquitin-specific protease 11
- TNFR:
-
tumor necrosis factor receptor
- TRAF2:
-
TNFα receptor-associated factor 2
- RIPK1:
-
receptor interacting protein kinase
- TRAIL:
-
TNFα-related apoptosis-inducing ligand
- TLR:
-
Toll-like receptor
- Smac:
-
second mitochondria-derived activator of caspases
- PI3K:
-
phosphoinositide 3-kinase
- TGFβ:
-
transforming growth factor-beta
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Acknowledgements
This research was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korean government (MEST) (2010-0017787) (J Song), by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs, Republic of Korea (A121387) (J Song), and by a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2012R1A6A3A04040105) (EWL). DS, J Seo, MJ, and HKL were partly supported by a fellowship from the Brain Korea 21 (BK21) PLUS program.
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Lee, EW., Seong, D., Seo, J. et al. USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics. Cell Death Differ 22, 1463–1476 (2015). https://doi.org/10.1038/cdd.2014.234
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DOI: https://doi.org/10.1038/cdd.2014.234
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