Statins decrease the expression of c-Myc protein in cancer cell lines
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Statins decrease the expression of c‑Myc protein in cancer cell lines Prema S. Rao1 · U. Subrahmanyeswara Rao1 Received: 15 July 2020 / Accepted: 9 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Statins are potent inhibitors of the mevalonate/cholesterol biosynthetic pathway and are widely prescribed for the prevention of cardiovascular diseases. Here, we carried out a comprehensive analysis of the effects of three statins, simvastatin, atorvastatin, and lovastatin, on six different cancer cell lines that include a P-glycoprotein-expressing, multidrug resistant variant of an ovarian cancer cell line. Incubation of all cancer cell lines with statins resulted in suppression of cell proliferation without inducing apoptotic cell death. The cell proliferation arrest could be reversed upon transfer of cells to statin-free growth media as well as by the supplementation of the growth media with mevalonate. Further analysis suggested that statins induced cell cycle arrest at G0/G1 phase in four cancer cell lines and the loss of c-Myc protein in three cancer cell lines. The c-Myc expression and the progression of cell division cycle were restored upon the addition of mevalonate to the culture media containing statins. Finally, cells incubated with statins contained an increased level of phosphorylated histone H2AX, an observation previously correlated to cellular senescence. Together, these data demonstrate that statins inhibit the mevalonate pathway which is tightly coupled to oxidative branch of the pentose phosphate pathway, c-Myc expression, cell division cycle progression, and cellular senescence. Implications of these observations in the application of statins as cancer therapeutics are discussed. Keywords Statins · c-Myc · HMG CoA reductase · Mevalonate pathway · Cell cycle
Introduction The mevalonate/cholesterol biosynthetic pathway proceeding from acetyl CoA to cholesterol, through the mevalonate intermediate, is an important anabolic pathway supplying cells with cholesterol necessary for the biosynthesis of biomembrane, bile acids, and steroid hormones for various physiological processes and precursor molecules for the synthesis of lipid isoprenoid intermediates in cell signaling pathways [1, 2]. This biosynthetic pathway is finely regulated at the conversion step of 3-hydroxy-3-methylglutarate (HMG) to mevalonate mediated by the HMG coenzyme A (CoA) reductase by the product inhibition mechanism. Drugs, such as statins, containing HMG-like moiety in Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11010-020-03940-2) contains supplementary material, which is available to authorized users. * U. Subrahmanyeswara Rao [email protected] 1
Department of Pharmaceutical Sciences, Appalachian College of Pharmacy, Oakwood, VA 24631, USA
their structures, inhibit the HMG CoA reductase potently at nanomolar concentrations, and are successfully utilized clinically to control atherosclerosis and increased risk of heart disease. Furt
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