Regulation of the Mevalonate Pathway for the Prevention of Breast Cancer

摘要

HMG-CoA reductase is the rate-limiting enzyme in cholesterol biosynthesis that catalyzes the production of mevalonate. In addition to being a precursor of cholesterol, mevalonate is required by cells for DNA synthesis and cell cycle progression. We have investigated the hypothesis that the mevalonate pathway may be a useful target for cancer prevention and therapy. We have shown that the dietary fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) as well as the dietary isoprenoid geraniol that inhibit cell proliferation, are inhibitors of HMG-CoA reductase activity in breast cancer cells. The inhibitory effects of EPA and geraniol on cell proliferation, however, are independent of mevalonate. DHA, on the other hand, inhibits proliferation at least in part, by inhibiting mevalonate synthesis. We showed that exogenous mevalonate promotes growth of breast cancer cells in nude mice as well as proliferation of the cells in culture. This was associated with an increase in the passage of cells through the G1 restriction point of the cell cycle. Mevalonate caused increased cyclin A- and E-associated CDK2 activity. This was mediated by increased phosphorylation of CDK2 and decreased binding of CDK2 to the CDK1 p21(sup cipl). These findings may be important since common treatments to lower serum cholesterol increase mevalonate synthesis.