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

Zoubeidi, Amina, Ettinger, Susan, Beraldi, Eliana, Hadaschik, Boris, Zardan, Anousheh, Klomp, Leo W.J., Nelson, Colleen, Rennie, Paul S., & Gleave, Martin E. (2010) Clusterin facilitates COMMD1 and I-kB degradation to enhance NF-kB activity in prostate cancer cells. Molecular Cancer Research, 8(1), pp. 119-130.

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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-κB nuclear translocation and transcriptional activity by serving as a ubiquitin-binding protein that enhances COMMD1 and I-κB proteasomal degradation by interacting with members of the SCF-βTrCP E3 ligase family. Knockdown of sCLU in prostate cancer cells stabilizes COMMD1 and I-κB, thereby sequestrating NF-κB in the cytoplasm and decreasing NF-κB transcriptional activity. Comparative microarray profiling of sCLU-overexpressing and sCLU-knockdown prostate cancer cells confirmed that the expression of many NF-κB–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-κB, thereby activating the canonical NF-κB pathway.

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36 citations in Web of Science®

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ID Code: 47679
Item Type: Journal Article
Keywords: prostate cancer, clusterin, COMMD1, I-kB, NF-kB
DOI: 10.1158/1541-7786.MCR-09-0277
ISSN: 1541-7786
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
Divisions: Past > QUT Faculties & Divisions > Faculty of Science and Technology
Deposited On: 12 Dec 2011 11:01
Last Modified: 05 Feb 2014 02:17

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