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Research Articles: Therapeutics

Sensitizing hormone-refractory prostate cancer cells to drug treatment by targeting 14-3-3

Department of Pharmacology and Toxicology, Indiana University Cancer Center and Walther Oncology Center, Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, Indiana

Requests for reprints: Jian-Ting Zhang, Department of Pharmacology and Toxicology, Indiana University Cancer Center, Indiana University School of Medicine, 1044 West Walnut Street, R4-166, Indianapolis, IN 46202. Phone: 317-278-4503; Fax: 317-274-8046. E-mail: jianzhan{at}iupui.edu

Abstract

Advanced and hormone-refractory prostate cancer has long been considered as a chemoresistant disease. Recently, it was found that 14-3-3 expression increases as prostate tumor progresses, and that 14-3-3 contributes significantly to drug resistance in breast cancers. We, thus, hypothesized that advanced and hormone-refractory prostate cancers may have an increased level of 14-3-3, which in turn may contribute to drug resistance in advanced and hormone-refractory prostate cancers. In this study, we tested this hypothesis and found that, indeed, the expression level of 14-3-3 in androgen-independent prostate cancer cell lines DU145, PC3, and CWR22RV are much higher than that in the androgen-dependent cell line LNCaP, and that the androgen-independent cells are more resistant to mitoxantrone and Adriamycin than the androgen-dependent cells. Depleting 14-3-3 expression in DU145 and CWR22RV by RNA interference significantly sensitized these cells to mitoxantrone and Adriamycin by abrogating G₂-M checkpoint and increasing apoptosis, whereas restoring 14-3-3 expression in LNCaP cells enhanced drug resistance. We also showed that 14-3-3 deficiency caused nuclear localization of Cdc2 and dephosphorylation of the Tyr¹⁵ residue upon DNA damage. Based on these studies, we propose that therapeutic intervention targeting 14-3-3 may be useful for sensitizing hormone-refractory prostate cancers to chemotherapy by both G₂-M checkpoint abrogation and apoptosis enhancement. [Mol Cancer Ther 2006;5(4):903–12]

Grant support: Showalter Research Trust Fund (B. Han), NIH grant CA94961 (J-T. Zhang), and Department of Defense grant W81XWH-05-1-0102 (J-T. Zhang).

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.

¹ Liu et al., Cancer Res, in press 2006.

Received 9/29/05; revised 12/14/05; accepted 1/25/06.

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