title: Lovastatin inhibits human B lymphoma cell proliferation by reducing intracellular ROS and TRPC6 expression.
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+).
authors: Department of Cardiology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, United States.
authors: Xiang
authors: X
authors: Song
authors: Department of Cardiology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, United States.
authors: Bing-Chen
authors: BC
authors: Liu
authors: Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, United States.
authors: Xiao-Yu
authors: XY
authors: Lu
authors: Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, United States; Department of Radiology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors: Li-Li
authors: LL
authors: Yang
authors: Department of Cardiology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors: Yu-Jia
authors: YJ
authors: Zhai
authors: Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, United States; Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, GA 30322, United States.
authors: Amity F
authors: AF
authors: Eaton
authors: Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, United States; Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, GA 30322, United States.
authors: Tiffany L
authors: TL
authors: Thai
authors: Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, United States; Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, GA 30322, United States.
authors: Douglas C
authors: DC
authors: Eaton
authors: Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, United States; Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, GA 30322, United States. Electronic address: heping.ma@emory.edu.
authors: He-Ping
authors: HP
authors: Ma
authors: Department of Radiology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Molecular Imaging of College of Heilongjiang, Harbin, Heilongjiang, China. Electronic address: shenbzh@vip.sina.com.
authors: Bao-Zhong
authors: BZ
authors: Shen
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D016393:Lymphoma, B-Cell / Q000473:pathology*; D018408:Patch-Clamp Techniques; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors*; D000074287:TRPC6 Cation Channel
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017382:Reactive Oxygen Species; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D008148:Lovastatin
keywords: Anti-cancer drugs; Cell cycle; Confocal microscopy; Intracellular calcium; Membrane cholesterol; Oxidative stress