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

Abstract

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 mevalonatetreated 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.HMG-CoA 1 reductase is the rate-limiting enzyme in cholesterol biosynthesis that catalyzes the formation of mevalonate (1). In addition to being a precursor of cholesterol, mevalonate is required for a number of cellular processes including DNA synthesis and proliferation (2). Mevalonate is also the precursor of non-sterol isoprenoids that have a variety of functions including prenylation of growth-regulating proteins and oncoproteins (3, 4). Elevated mevalonate synthesis has been reported in malignant breast (5), lung (6), leukemia and lymphoma (7), and hepatoma cells (8). Whether increased mevalonate synthesis occurs in malignant cells simply 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.HMG-CoA reductase is regulated through a multivalent feedback mechanism that is controlled, in part, by intracellular cholesterol levels (1). Cells meet their cholesterol requirements by de novo synthesis or by uptake from plasma of cholesterolrich low density lipoprotein. A fall in circulating levels of low density lipoprotein causes a decrease in its uptake, and the resultant drop in intracellular cholesterol levels leads to a compensatory stimulation of mevalonate synthesis through upregulation of HMG-CoA reductase (1). We have shown that a diet rich in cholesterol that raised circulating cholesterol levels also significantly decreased mammary gland HMG-CoA reductase activity (5) and inhibited the development of chemically induced mammary tumors in rats (5, 9). We have also shown in mice that a diet rich in cholesterol protects against the development of chemically induced preneoplastic lesio...

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