Arsenic, cadmium, mercury and nickel stimulate cell growth via NADPH oxidase activation

•The SH-reactive metals arsenic, cadmium, mercury and nickel activate NADPH oxidase (NOX).•Low concentrations of metals stimulate cell proliferation in NOX-proficient cells but not in NOX-deficient cells.•Addition of NOX-silencing RNA sequences or the NOX-specific inhibitor DPI attenuate metal-induced cell proliferation.

Exposure to metals and metalloids including arsenic, cadmium, mercury, and nickel has been a worldwide health problem for several decades. The aim of this study was to learn how metal-induced oxidative stress triggers cell proliferation, a process of great significance for cancer.NADPH oxidase (NOX) activity and cell proliferation were measured as endpoints in both NOX-deficient and NOX-proficient cells. The X chromosome linked CGD (X-CGD) human promyelocytic leukemia PLB-985 cells lacking gp91phox and the X-CGD cells re-transfected with gp91phox (X-CGD-gp91phox) were used together with immortalized human keratinocyte cells (HaCaT). The cells were exposed to different concentrations of the metals alone or together with the NOX inhibitor, diphenyleneiodonium (DPI).We found that the studied metals increased NOX activity. They stimulated cell proliferation in HaCaT and X-CGD-gp91phox cells at concentrations below 1 μM but not in the X-CGD cells that lack functional NOX. Addition of DPI attenuated the metal-induced cell proliferation. At concentrations above 1 μM these metals inhibited cell proliferation.Based on these findings, we propose that many environmental pollutants, including metals and also endogenous NOX-activators such as oxidants and growth factors, interfere with cell growth kinetics by increasing the levels of the diffusible molecule H2O2. Here, we provide evidence that NOXs is central to the mechanism of metal-mediated reactive oxygen species production and stimulation of cell proliferation.