title: Metformin decreases growth of pancreatic cancer cells by decreasing reactive oxygen species: Role of NOX4.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our findings suggest that metformin decreases cell survival by reducing ROS production, in part through down regulation of NOX4 protein expression.
authors.affiliation: Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Guanjun
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: sjacoby43@gmail.com.
authors.forename: Susan
authors.initials: S
authors.lastname: Lanza-Jacoby
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D008687:Metformin; D013482:Superoxide Dismutase; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D005947:Glucose
keywords: Cell survival; Metformin; NOX4; Oxidative stress; Pancreatic cancer