USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

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.

The deubiquitinating enzyme USP20 stabilizes ULK1 and promotes autophagy initiation

“…The in vitro deubiquitination assay was performed as described previously . Briefly, ubiquitinated Flag‐ULK1, Flag‐USP20 wild‐type (WT), and Flag‐USP20 catalytically inactive (CI) proteins were isolated from HEK293 cells transiently expressing Flag‐ULK1 and HA‐Ub, the plasmid encoding Flag‐USP20 wild‐type (WT) alone, and plasmid encoding the Flag‐USP20 catalytically inactive (CI) form alone, respectively.…”

Pellino-1 confers chemoresistance in lung cancer cells by upregulating cIAP2 through Lys63-mediated polyubiquitination

“…cIAP expression is known to be regulated at the transcriptional, translational, and post-translational levels [29–31]. This study for the first time demonstrated that cIAP2 is directly stabilized through Pellino-1-mediated Lys63-polyubiquitination.…”

Potency and Selectivity of SMAC/DIABLO Mimetics in Solid Tumor Therapy

“…Thus, a mass of work concentrated on the key mechanisms of therapeutic resistance to SMs in cancer cells. Previous studies confirmed that some cancer cells evade SM-induced cell death via stabilization of cIAP2 [85][86][87]. Some resistant cell lines have such an intense tendency to upregulate cIAP2, while sensitive cells seem to be less susceptible to signals that upregulate cIAP2.…”

“…In the absence of cIAP1 or TRAF2, the newly generated cIAP2 is no longer downregulated by SMs. Another report showed that overexpression of ubiquitin-specific protease 11 (USP11) led to stabilization of cIAP2 and promoted SM therapeutic resistance [86].…”