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.
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.
Duncan
Robin E
RE
Departments of Nutritional Sciences and Medical Biophysics, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
El-Sohemy
Ahmed
A
Archer
Michael C
MC
D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D019925:Cyclin A; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D016193:G1 Phase; D015870:Gene Expression; D006801:Humans; D007163:Immunosorbent Techniques; D008798:Mevalonic Acid / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011494:Protein Kinases; C102333:histone H1 kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D008798:Mevalonic Acid