Lovastatin inhibits human B lymphoma cell proliferation by reducing intracellular ROS and TRPC6 expression

• Authors: Xiang Song, Harbin Medical University; Bing-Chen Liu, Harbin Medical University; Xiao-Yu Lu, Emory University; Li-Li Yang, Emory University; Yujia Zhai, Emory University; Amity F. Eaton, Emory University; Tiffany Thai, Emory University; Douglas C Eaton, Emory University; He-Ping Ma, Emory University; Bao-Zhong Shen, Harbin Medical University
• Journal Title: Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids
• Volume: Volume 1843, Number 5
• Publisher: Elsevier: 12 months | 2014-05-01, Pages 894-901
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.bbamcr.2014.02.002
• Subjects: Chemistry, Biochemistry; Chemistry, Pharmaceutical
• Keywords: Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; Cell Biology; Anti-cancer drugs; Cell cycle; Membrane cholesterol; Oxidative stress; Intracellular calcium; Confocal microscopy; IN-VITRO; STATIN USE; CANCER; CHANNELS; APOPTOSIS; RISK; ACTIVATION; CHOLESTEROL; ARREST; STRESS

Abstract

Clinical evidence suggests that statins reduce cancer incidence and mortality. However, there is lack of in vitro data to show the mechanism by which statins can reduce the malignancies of cancer cells. We used a human B lymphoma Daudi cells as a model and found that lovastatin inhibited, whereas exogenous cholesterol (Cho) stimulated, proliferation cell cycle progression in control Daudi cells, but not in the cells when transient receptor potential canonical 6 (TRPC6) channel was knocked down. Lovastatin decreased, whereas Cho increased, the levels of intracellular reactive oxygen species (ROS) respectively by decreasing or increasing the expression of p47-phox and gp91-phox (NOX2). Reducing intracellular ROS with either a mimetic superoxide dismutase (TEMPOL) or an NADPH oxidase inhibitor (apocynin) inhibited cell proliferation, particularly in Cho-treated cells. The effects of TEMPOL or apocynin were mimicked by inhibition of TRPC6 with SKF-96365. Lovastatin decreased TRPC6 expression and activity via a Cho-dependent mechanism, whereas Cho increased TRPC6 expression and activity via an ROS-dependent mechanism. Consistent with the fact that TRPC6 is a Ca 2+ -permeable channel, lovastatin decreased, but Cho increased, intracellular Ca 2+ also via ROS. These data suggest that lovastatin inhibits malignant B cell proliferation by reducing membrane Cho, intracellular ROS, TRPC6 expression and activity, and intracellular Ca 2+ .