Statin-induced breast cancer cell death: role of inducible nitric oxide and arginase-dependent pathways. Cancer Res 2007 Aug 01;67(15):7386-94
Date
08/03/2007Pubmed ID
17671209DOI
10.1158/0008-5472.CAN-07-0993Scopus ID
2-s2.0-34547641739 (requires institutional sign-in at Scopus site) 135 CitationsAbstract
Statins are widely used cholesterol-lowering drugs that selectively inhibit the enzyme 3-hydroxy-3-methylglutaryl CoA reductase, leading to decreased cholesterol biosynthesis. Emerging data indicate that statins stimulate apoptotic cell death in several types of proliferating tumor cells, including breast cancer cells, which is independent of its cholesterol-lowering property. The objective here was to elucidate the molecular mechanism(s) by which statins induce breast cancer cell death. Fluvastatin and simvastatin (5-10 mumol/L) treatment enhanced the caspase-3-like activity and DNA fragmentation in MCF-7 cells, and significantly inhibited the proliferation of MCF-7 cells but not MCF-10 cells (noncancerous epithelial cells). Statin-induced cytotoxic effects were reversed by mevalonate, an immediate metabolic product of the acetyl CoA/3-hydroxy-3-methylglutaryl CoA reductase reaction. Both simvastatin and fluvastatin enhanced nitric oxide ((.)NO) levels which were inhibited by mevalonate. Statin-induced (.)NO and tumor cell cytotoxicity were inhibited by 1400W, a more specific inhibitor of inducible nitric oxide synthase (iNOS or NOS II). Both fluvastatin and simvastatin increased iNOS mRNA and protein expression. Stimulation of iNOS by statins via inhibition of geranylgeranylation by GGTI-298, but not via inhibition of farnesylation by FTI-277, enhanced the proapoptotic effects of statins in MCF-7 cells. Statin-mediated antiproliferative and proapoptotic effects were exacerbated by sepiapterin, a precursor of tetrahydrobiopterin, an essential cofactor of (.)NO biosynthesis by NOS. We conclude that iNOS-mediated (.)NO is responsible in part for the proapoptotic, tumoricidal, and antiproliferative effects of statins in MCF-7 cells.
Author List
Kotamraju S, Williams CL, Kalyanaraman BAuthors
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of WisconsinCarol L. Williams PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Anticholesteremic AgentsAntioxidants
Apoptosis
Arginase
Blotting, Western
Breast Neoplasms
Caspase 3
Cell Adhesion
Cell Cycle
Cells, Cultured
Colony-Forming Units Assay
Fatty Acids, Monounsaturated
Humans
In Situ Nick-End Labeling
Indoles
Mevalonic Acid
Nitric Oxide
Nitric Oxide Synthase Type II
Polyisoprenyl Phosphates
Protein Prenylation
RNA, Messenger
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Simvastatin