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J. Biol. Chem., Vol. 279, Issue 32, 33079-33084, August 6, 2004

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Mevalonate Promotes the Growth of Tumors Derived from Human Cancer Cells in Vivo and Stimulates Proliferation in Vitro with Enhanced Cyclin-dependent Kinase-2 Activity^*

Robin E. Duncan, Ahmed El-Sohemy, and Michael C. Archer¶

From the Departments of Nutritional Sciences and Medical Biophysics, University of Toronto, Toronto, Ontario M5S 3E2, Canada

Malignant cells are known to have elevated rates of mevalonate synthesis because of increased levels and catalytic efficiency of 3-hydroxy-3-methylglutaryl-CoA reductase. Whether this increased mevalonate synthesis occurs as a consequence of increased requirements for a mevalonate-derived metabolite in response to rapid growth or whether mevalonate promotes the growth of tumor cells is unknown. To address this question, we administered mevalonate via miniosmotic pumps to nude mice inoculated with MDA-MB-435 human cancer cells. After 13 weeks of growth, tumors in mevalonate-treated mice were significantly larger than tumors in saline-treated, control mice (1.52 ± 0.26 g versus 0.81 ± 0.27 g respectively, p < 0.05). The cancer cells treated in culture with mevalonate also demonstrated increased proliferation rates associated with accelerated entry of cells into S phase. These cells had enhanced total and cyclin A-immunoprecipitable cyclin-dependent kinase-2 (CDK-2) activity, increased activating phosphorylation of CDK-2, and decreased inhibitory binding of CDK-2 to p21^Cip1. Our findings demonstrate that mevalonate promotes tumor growth and suggest that an increase in mevalonate synthesis in extrahepatic tissues following cholesterol-lowering therapy may explain the elevated risk of cancer shown in some studies.

Received for publication, January 1, 2004 , and in revised form, May 19, 2004.

^* This work was supported by U. S. Army Medical Research Acquisition Activity Grant DAMD17-99-1-9409. 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.

^¶ Recipient of a Natural Sciences and Engineering Research Council of Canada Industrial Research Chair and supported by the member companies of the program in Food Safety, Nutrition and Regulatory Affairs of the University of Toronto. To whom correspondence should be addressed: Dept. of Nutritional Sciences, University of Toronto, FitzGerald Bldg., 150 College St., Toronto, Ontario M5S 3E2, Canada. Tel.: 416-978-8195; Fax: 416-971-2366; E-mail: m.archer{at}utoronto.ca.

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