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

E. W. Lee, D. Seong, J. Seo, M. Jeong, H. K. Lee, J. Song

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1463-1476
Number of pages14
JournalCell Death and Differentiation
Volume22
Issue number9
DOIs
Publication statusPublished - 2015 Sep 11

Fingerprint

Ubiquitin-Specific Proteases
Inhibitor of Apoptosis Proteins
Neoplasms
Apoptosis
Cell Line
MAP Kinase Signaling System
Heterografts
Colorectal Neoplasms
Melanoma
Cell Survival
Down-Regulation
Growth

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Lee, E. W. ; Seong, D. ; Seo, J. ; Jeong, M. ; Lee, H. K. ; Song, J. / USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics. In: Cell Death and Differentiation. 2015 ; Vol. 22, No. 9. pp. 1463-1476.
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USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics. / Lee, E. W.; Seong, D.; Seo, J.; Jeong, M.; Lee, H. K.; Song, J.

In: Cell Death and Differentiation, Vol. 22, No. 9, 11.09.2015, p. 1463-1476.

Research output: Contribution to journalArticle

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AU - Song, J.

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