Oxidative stress induces apoptosis via calpain- and caspase-3-mediated cleavage of ATM in pancreatic acinar cells.

Oxidative stress-induced DNA cleavage and apoptosis in pancreatic acinar cells has been implicated in the pathogenesis of acute pancreatitis. Thus, an efficient DNA repair process is key to prevention of apoptotic pancreatic acinar cell death. Ataxia telangiectasia mutated (ATM), a sensor of DNA breaks, functions by recruiting DNA repair proteins to initiate the DNA repair process. In the present study, we investigated whether H2O2 produced by the action of glucose oxidase on α-D-glucose (G/GO) induces apoptosis in pancreatic acinar AR42J cells through an alteration of the level of ATM. As a result, G/GO induced apoptosis by promoting a loss of cell viability, increase in Bax, decrease in Bcl-2, cleavage of poly (ADP-ribose) polymerase (PARP) and fragmentation of DNA. In addition, ATM cleavage along with elevated levels of calpain and caspase-3 activity was induced by G/GO. By using ATM siRNA, we demonstrated that reduction in ATM levels enhanced G/GO-induced apoptosis. Moreover, inhibition of calpain activity by calpeptin or calpastatin, or by inhibition of caspase-3 with z-DEVD, suppressed G/GO-induced apoptosis and ATM cleavage. Collectively, these findings suggest that proteolysis of ATM is the underlying mechanism of apoptosis of pancreatic acinar cells caused by exposure to oxidative stress.