Metformin decreases growth of pancreatic cancer cells by decreasing reactive oxygen species: Role of NOX4

• Published in: Biochemical and biophysical research communications Vol. 465; no. 1; pp. 41 - 46
• Main Authors: Cheng, Guanjun, Lanza-Jacoby, Susan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.09.2015
• Subjects: Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation; Cell survival; Cell Survival - drug effects; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Gene Expression Regulation, Neoplastic; Glucose - metabolism; Glucose - toxicity; Humans; Hypoglycemic Agents - pharmacology; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Metformin; Metformin - pharmacology; NADPH Oxidase 2; NADPH Oxidase 4; NADPH Oxidases - antagonists & inhibitors; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; NOX4; Oxidative stress; Pancreas - drug effects; Pancreas - metabolism; Pancreas - pathology; Pancreatic cancer; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Signal Transduction; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Oxidative stress; NOX4; Cell survival; Metformin; Pancreatic cancer
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2015.07.118

Retrospective epidemiologic studies show that metformin reduced the incidence of pancreatic cancer in diabetic patients. One potential mechanism may be by altering reactive oxygen species (ROS) and apoptosis. In this in vitro study, we explore the role of ROS and apoptosis in mediating the growth-inhibitory effects of metformin in pancreatic cancer cells. We cultured MIA PaCa and Panc1 pancreatic cancer cells in medium containing physiological concentrations of glucose (5 mM) or supra-physiological concentrations of glucose and then treated cells with metformin. Cell viability, ROS production, apoptosis, and protein levels of manganese superoxide dismutase (MnSOD), NADPH oxidase (NOX) 2, and NOX4 were measured. Metformin decreased viability of MIA PaCa and Panc1 cells under physiological glucose conditions in comparison to untreated cells; metformin did not have any effect on human pancreatic normal epithelial (HPNE) cells. The decrease in cell survival was associated with decreased intracellular ROS, increased protein levels of MnSOD, and decreased levels of NOX2 and NOX4 proteins in MIA PaCa and Panc1 cells but not HPNE cells. Transfecting MIA PaCa and Panc1 cells with pcDNA3NOX4 protected against the anti-survival effects of metformin. Our findings suggest that metformin decreases cell survival by reducing ROS production, in part through down regulation of NOX4 protein expression. •We studied the role of metformin in reducing ROS and pancreatic cell growth.•Metformin-induced decrease in cell survival is associated with reduced ROS.•Metformin increased expression of MnSOD, Catalase, and decreased NOX2 and NOX4.•Overexpression of NOX4 partially abrogated the anti-survival effects of metformin.•Metformin inhibits cell survival by reducing ROS, in part through reduced NOX4.