Clusterin facilitates COMMD1 and I-kappaB degradation to enhance NF-kappaB activity in prostate cancer cells.

Abstract

Secretory clusterin (sCLU) is a stress-activated, cytoprotective chaperone that confers broad-spectrum cancer treatment resistance, and its targeted inhibitor (OGX-011) is currently in phase II trials for prostate, lung, and breast cancer. However, the molecular mechanisms by which sCLU inhibits treatment-induced apoptosis in prostate cancer remain incompletely defined. We report that sCLU increases NF-kappaB nuclear translocation and transcriptional activity by serving as a ubiquitin-binding protein that enhances COMMD1 and I-kappaB proteasomal degradation by interacting with members of the SCF-betaTrCP E3 ligase family. Knockdown of sCLU in prostate cancer cells stabilizes COMMD1 and I-kappaB, thereby sequestrating NF-kappaB in the cytoplasm and decreasing NF-kappaB transcriptional activity. Comparative microarray profiling of sCLU-overexpressing and sCLU-knockdown prostate cancer cells confirmed that the expression of many NF-kappaB-regulated genes positively correlates with sCLU levels. We propose that elevated levels of sCLU promote prostate cancer cell survival by facilitating degradation of COMMD1 and I-kappaB, thereby activating the canonical NF-kappaB pathway.

• Authors: Amina Zoubeidi, Susan Ettinger, Eliana Beraldi, Boris Hadaschik, Anousheh Zardan, Leo W J Klomp, Colleen C Nelson, Paul S Rennie, Martin E Gleave
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 8 Issue 1 Pg. 119-30 (Jan 2010) ISSN: 1557-3125 [Electronic] United States
• PMID: 20068069 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• COMMD1 protein, human
• Carrier Proteins
• Clusterin
• I-kappa B Proteins
• NF-kappa B
• RNA, Small Interfering
• Ubiquitin
• Proteasome Endopeptidase Complex

Topics

• Adaptor Proteins, Signal Transducing
• Carcinoma (genetics, metabolism, pathology)
• Carrier Proteins (metabolism)
• Cell Line, Tumor
• Clusterin (antagonists & inhibitors, genetics, metabolism, physiology)
• HeLa Cells
• Humans
• I-kappa B Proteins (metabolism)
• Male
• Models, Biological
• NF-kappa B (metabolism)
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Binding
• Protein Processing, Post-Translational (drug effects, genetics)
• Protein Stability (drug effects)
• RNA, Small Interfering (pharmacology)
• Ubiquitin (metabolism)
• Ubiquitination (genetics)