Clusterin Facilitates COMMD1 and I-kappa B Degradation to Enhance NF-kappa B 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-kappa B nuclear translocation and transcriptional activity by serving as a ubiquitin-binding protein that enhances COMMD1 and I-kappa B proteasomal degradation by interacting with members of the SCF-beta TrCP E3 ligase family. Knockdown of sCLU in prostate cancer cells stabilizes COMMD1 and I-kappa B, thereby sequestrating NF-kappa B in the cytoplasm and decreasing NF-kappa B transcriptional activity. Comparative microarray profiling of sCLU-overexpressing and sCLU-knockdown prostate cancer cells confirmed that the expression of many NF-kappa B-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-kappa B, thereby activating the canonical NF-kappa B pathway. Mol Cancer Res; 8(1); 119-30. (C) 2010 AACR.