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Research Articles: Therapeutics, Targets, and Development

Clusterin mediates TRAIL resistance in prostate tumor cells

Immunology Program, H. Lee Moffitt Cancer Center and Department of Interdisciplinary, Oncology, University of South Florida College of Medicine, Tampa, Florida

Requests for reprints: Julie Y. Djeu, Immunology Program, H. Lee Moffitt Cancer Center, MRC-4 East, 12902 Magnolia Drive, Tampa, FL 33612. Phone: 813-979-3041; Fax: 813-979-7264. E-mail: djeu{at}moffitt.usf.edu

Abstract

One of the major obstacles in curing prostate cancer is the development of drug resistance to docetaxel, which is the gold standard for the treatment of this disease. It is not only imperative to discover the molecular basis of resistance but also to find therapeutic agents that can disrupt the resistant pathways. Based on initial findings that docetaxel-resistant PC3-DR and DU145-DR prostate tumor cell lines express tumor necrosis factor–related apoptosis inducing ligand (TRAIL) receptors, we examined whether TRAIL could be used as an alternative method to kill PC3-DR and DU145-DR cells. However, these tumor cells were found to be TRAIL resistant. Because PC3-DR and DU-145-DR cells were previously shown by us to be clusterin positive, we examined if clusterin could play a role in TRAIL resistance. We found that resveratrol could sensitize docetaxel-resistant tumor cells to TRAIL, and it worked by blocking clusterin expression. In particular, small interfering RNA clusterin expression in the cell lines was sufficient to produce apoptosis by TRAIL. Further analysis indicated that resveratrol functions as an effective tyrosine kinase inhibitor, similar to its analogue, piceatannol, and could inhibit Src and Jak kinases, thus resulting in loss of Stat1 activation. We have shown earlier that Stat1 is essential for gene transcription of clusterin. These results, taken together, show that resveratrol could be a useful new therapeutic agent to combat docetaxel resistance. [Mol Cancer Ther 2007;6(11):2938–47]

Grant support: NIH grants CA98080 and AI056213.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 5/28/07; revised 8/10/07; accepted 10/ 1/07.

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