Statins decrease the expression of c-Myc protein in cancer cell lines

• Published in: Molecular and cellular biochemistry 2021-02, Vol.476 (2), p.743-755
• Main Authors: Rao, Prema S., Rao, U. Subrahmanyeswara
• Format: Article
• Language: English
• Subjects: Analysis; Antilipemic agents; Apoptosis; Atorvastatin; Atorvastatin - pharmacology; Biochemistry; Biomedical and Life Sciences; Biotechnology; c-Myc protein; Cancer; Cardiology; Cardiovascular diseases; Cell culture; Cell cycle; Cell Cycle - drug effects; Cell death; Cell division; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cholesterol; Culture media; Fluvastatin - pharmacology; G1 phase; Glycoproteins; Growth media; Histone H2A; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Life Sciences; Lovastatin; Lovastatin - pharmacology; Medical Biochemistry; Mevalonate pathway; Mevalonic acid; Mevalonic Acid - metabolism; Multidrug resistance; Myc protein; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Oncology; Ovarian cancer; P-Glycoprotein; Pentose; Pentose phosphate pathway; Proteins; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - biosynthesis; Proto-Oncogene Proteins c-myc - metabolism; Senescence; Simvastatin; Simvastatin - pharmacology; Statins; Tumor cell lines
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-020-03940-2

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.