期刊
MOLECULAR AND CELLULAR BIOCHEMISTRY
卷 476, 期 2, 页码 743-755出版社
SPRINGER
DOI: 10.1007/s11010-020-03940-2
关键词
Statins; c-Myc; HMG CoA reductase; Mevalonate pathway; Cell cycle
类别
资金
- College Administration
Statins inhibit cancer cell proliferation by suppressing the mevalonate/cholesterol biosynthesis pathway, leading to cell cycle arrest at G0/G1 phase, reduction of c-Myc protein expression, and induction of cellular senescence.
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 aP-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.
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