Clusterin facilitates COMMD1 and I-kappaB degradation to enhance NF-kappaB activity in prostate cancer cells.
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.
Mesh Terms:
Carcinoma, Carrier Proteins, Cell Line, Tumor, Clusterin, Hela Cells, Humans, I-kappa B Proteins, Male, Models, Biological, NF-kappa B, Prostatic Neoplasms, Proteasome Endopeptidase Complex, Protein Binding, Protein Processing, Post-Translational, Protein Stability, RNA, Small Interfering, Ubiquitin, Ubiquitination
Carcinoma, Carrier Proteins, Cell Line, Tumor, Clusterin, Hela Cells, Humans, I-kappa B Proteins, Male, Models, Biological, NF-kappa B, Prostatic Neoplasms, Proteasome Endopeptidase Complex, Protein Binding, Protein Processing, Post-Translational, Protein Stability, RNA, Small Interfering, Ubiquitin, Ubiquitination
Mol. Cancer Res.
Date: Jan. 01, 2010
PubMed ID: 20068069
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