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Research Articles: Therapeutics, Targets, and Development

Increased expression of cyclin B1 sensitizes prostate cancer cells to apoptosis induced by chemotherapy

¹ Geriatric Research, Education, and Clinical Center and Research Service, VA Medical Center; ² Department of Medicine, ³ Department of Molecular and Cellular Pharmacology, and ⁴ Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine; and ⁵ South Florida VA Foundation, Miami, Florida

Requests for reprints: Carlos Perez-Stable, Veterans Affairs Medical Center, GRECC (11-GRC), 1201 Northwest 16 Street, Miami, FL 33125. Phone: 305-324-4455, ext. 4391; Fax: 305-575-3365. E-mail: cperez{at}med.miami.edu

Abstract

Chemotherapeutic drugs ideally should take advantage of the differences between transformed and normal cells and induce apoptosis only in cancer cells. One such difference may be the overexpression of cyclin B1 protein in cancer cells, which is required for the proper progression through mitosis. Previously, we showed that treatment of human prostate cancer cells with 2-methoxyestradiol (2-ME) or docetaxel results in an accumulation of cyclin B1 protein and an increase in cyclin B1 kinase activity, followed by induction of apoptotic cell death. Inhibition of cyclin B1 kinase lowers apoptosis induced by 2-ME and docetaxel. In this study, we established a positive correlation between cyclin B1 protein and apoptosis induced by chemotherapy in prostate cancer cells. There is minimal cyclin B1 and induction of apoptosis by chemotherapy in nontransformed cells. LNCaP and PC-3 prostate cancer cells stably overexpressing cyclin B1 are more sensitive to apoptosis induced by chemotherapy. LNCaP cells expressing cyclin B1 small interfering RNA to lower cyclin B1 protein or dominant negative cyclin-dependent kinase 1 to inhibit cyclin B1 kinase show a decrease in apoptosis. Increased sensitivity to apoptosis by overexpression of cyclin B1 may be due to lower Bcl-2, higher p53, and decreased neuroendocrine differentiation. We suggest that a cancer-specific mechanism whereby 2-ME and docetaxel may exert anti–prostate cancer activity is the deregulated activation of cyclin B1 kinase, leading to the induction of apoptotic cell death. Our results also suggest that higher levels of cyclin B1 in prostate cancer cells may be a good prognostic marker for chemotherapy. [Mol Cancer Ther 2007;6(5):1534–43]

Grant support: VA Merit Review grant 026901, Department of Defense grant DAMD17-03-1-0179, and Aventis Pharmaceuticals grant GIA 60025 (C. Perez-Stable).

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 11/27/06; revised 2/23/07; accepted 3/23/07.