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
Open accessAbstract
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.
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Cholesterol deprivation can inhibit tumor growth, decrease phosphorylation of AKT, promote apoptosis, decrease Bcl-xl, downregulate caspase 3 activation, or hinder entry of cells into S phase.
“cholesterol deprivation can inhibit tumor growth, decrease the phosphorylation of AKT, promote apoptosis62, decrease Bcl-xl, downregulate caspase 3 activation63, or hinder entry of cells into the S phase64.”
From RETRACTED ARTICLE: Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression (2020) · cites this paper as [64]
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References 63 · Cited by 113
Research works printed but not linked: 3
- Quesney-Huneeus, V. R., Wiley, M. H., and Siperstein, M. D. (1979) Proc. Natl. Acad. Sci. U. S. A. 76, 5056 -5060
- Casey, P. J., Solski, P. A., Der, C. J., and Buss, J. E. (1989) Proc. Natl. Acad. Sci. U. S. A. 86, 8323-8327
- Duncan, R. E., El-Sohemy, A., and Archer, M. (2004) J. Pharmacol. Toxicol. Methods, in press
- Authors
- Duncan, R. E., El-Sohemy, A., & Archer, M. C.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Archer, Michael C.
- ORCID
- Duncan, Robin E.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-08
- Volume
- 279
- Issue
- 32
- Pages
- 33079-33084
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2047594294
- Cited by
- 113
- References
- 63
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 11 · 2018: 3 · 2017: 4 · 2016: 9 · 2015: 10 · 2014: 7 · 2013: 5 · 2012: 6
- FWCI
- 2.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- University of Toronto
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- mevalonate, tumor growth, CDK2, HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-CoA reductase, cell proliferation, S phase entry, p21, cholesterol-lowering therapy, cancer risk
- MeSH terms
- Animals, Cell Division, Flow Cytometry, Humans, Immunosorbent Techniques, Mevalonic Acid, Mice, Nude, Neoplasm Transplantation, Neoplasms, Phosphorylation, Protein Kinases, Tumor Cells, Cultured, Gene Expression, G1 Phase, S Phase, Cyclins, Cyclin A, CDC2-CDC28 Kinases, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase 2, Mice
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