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.
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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|Item Type:||Journal Article|
|Keywords:||prostate cancer, clusterin, COMMD1, I-kB, NF-kB|
|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 21:01|
|Last Modified:||05 Feb 2014 12:17|
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