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.