Induction Of Clusterin By AKT--Role In Cytoprotection Against Docetaxel In Prostate Tumor Cells

Main Category: Prostate / Prostate Cancer
Article Date: 11 Aug 2010 - 1:00 PDT


In the online edition of Molecular Cancer Therapeutics, Dr. Bin Zhong and associates report a link between the signal transduction protein AKT and the androgen receptor chaperone protein clusterin (CLU). Two forms of CLU exist; one is secreted (sCLU) and the other localizes in the nucleus (nCLU). sCLU is associated with chemoresistance and overexpression of sCLU induces androgen resistance. This report investigated whether AKT is involved in sCLU gene expression and resistance to doxetaxel chemotherapy in vitro. In addition, they sought a link between AKT and transcription factor STAT1.

The studies were performed in androgen independent DU145 and PC3 cells. Also, dominant negative AKT (DN-AKT) and drug resistant (DR) DU145 and PC3 cell lines were used. They found that activated AKT was strongly increased in the DR cell lines and sCLU was also similarly increased compared with control DU145 and PC3 cells. Cell treatment with the AKT inhibitor API-2 resulted in dose-dependent inhibition of activated AKT and sCLU expression. Pretreatment with API-2 in DR cells followed by chemotherapy showed increased cell death, suggesting that the AKT induced sCLU expression and chemoresistance is reversible by inhibiting AKT activation. Transfection of DN-AKT into DR cells resulted in suppressed sCLU expression supporting regulation of sCLU by AKT. The downregulation of sCLU protein by AKT was confirmed to be at the transcriptional level. To support the link between AKT and chemoresistance, they demonstrated that DN-AKT chemosensitized CaP cells to docetaxel chemotherapy by caspase-3 induced cell death. This further supports involvement of AKT in the docetaxel resistance of CaP cells. However, they also found that once sCLU is present, AKT inhibition cannot induce cell death with docetaxel, suggesting that sCLU can overcome API-2 cell death and is a key mediator in AKT regulated docetaxel resistance. The investigators had previously reported that STAT1 is the transcriptional factor necessary for sCLU gene expression in DR CaP cells, and in this report they find that AKT is upstream of STAT1 and controls it.

Zhong B, Sallman DA, Gilvary DL, Pernazza D, Sahakian E, Fritz D, Cheng JQ, Trougakos I, Wei S, Djeu JY

Mol Cancer Ther. 2010 Jun;9(6):1831-41.
doi: 10.1158/1535-7163.MCT-09-0880

Written by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

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