Induction of clusterin by AKT - Role in cytoprotection against docetaxel in prostate tumor cells

Bin Zhong, David A. Sallman, Danielle L. Gilvary, Daniele Pernazza, Eva Sahakian, Dillon Fritz, Jin Q. Cheng, Ioannis Trougakos, Sheng Wei, Julie Y. Djeu

    Research output: Contribution to journalArticlepeer-review

    46 Scopus citations

    Abstract

    Clusterin (CLU), in its cytoplasmic form, is abundant in many advanced cancers and has been established to be cytoprotective against chemotherapeutic agents including docetaxel. However, little is known of the mechanism of its induction. Here, we provide evidence that AKT plays a critical role in upregulating cytoplasmic/secretory sCLU, which is responsible for docetaxel resistance. Western blot analysis indicated that docetaxel-resistant sublines derived from DU145 and PC3 prostate tumor cell lines displayed a markedly increased phospho-AKT level closely accompanied by heightened sCLU expression when compared with parental cells. To examine if AKT has a role in sCLU expression, AKT blockade was done by treatment with a specific inhibitor, API-2, or dominant-negative AKT transduction before analysis of sCLU gene expression. Loss of AKT function resulted in loss of sCLU and was accompanied by chemosensitization to docetaxel and increased cell death via a caspase-3-dependent pathway. To confirm that AKT affected resistance to docetaxel through sCLU and not through other mediators, tumor cells were first transfected with full-length CLU for overexpression and then treated with the AKT inhibitor API-2. We found that once sCLU was overexpressed, API-2 could not chemosensitize the tumor cells to docetaxel. Thus, the chemoresistance to docetaxel is mediated by sCLU and it can be induced by AKT. Lastly, AKT was found to mediate sCLU induction via signal transducer and activator of transcription 1 activation, which we have earlier shown to drive sCLU gene expression. These results identify a previously unrecognized pathway linking AKT to cytoprotection by sCLU in tumor cells.

    Original languageEnglish (US)
    Pages (from-to)1831-1841
    Number of pages11
    JournalMolecular Cancer Therapeutics
    Volume9
    Issue number6
    DOIs
    StatePublished - Jun 1 2010

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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