Calcium and adenosine triphosphate control of cellular pathology: asparaginase-induced pancreatitis elicited via protease-activated receptor 2

Abstract

Exocytotic secretion of digestive enzymes from pancreatic acinar cells is elicited by physiological cytosolic Ca 2+ signals, occurring as repetitive short-lasting spikes largely confined to the secretory granule region, that stimulate mitochondrial adenosine triphosphate (ATP) production. By contrast, sustained global cytosolic Ca 2+ elevations decrease ATP levels and cause necrosis, leading to the disease acute pancreatitis (AP). Toxic Ca 2+ signals can be evoked by products of alcohol and fatty acids as well as bile acids. Here, we have investigated the mechanism by which l -asparaginase evokes AP. Asparaginase is an essential element in the successful treatment of acute lymphoblastic leukaemia, the most common type of cancer affecting children, but AP is a side-effect occurring in about 5–10% of cases. Like other pancreatitis-inducing agents, asparaginase evoked intracellular Ca 2+ release followed by Ca 2+ entry and also substantially reduced Ca 2+ extrusion because of decreased intracellular ATP levels. The toxic Ca 2+ signals caused extensive necrosis. The asparaginase-induced pathology depended on protease-activated receptor 2 and its inhibition prevented the toxic Ca 2+ signals and necrosis. We tested the effects of inhibiting the Ca 2+ release-activated Ca 2+ entry by the Ca 2+ channel inhibitor GSK-7975A. This markedly reduced asparaginase-induced Ca 2+ entry and also protected effectively against the development of necrosis. This article is part of the themed issue ‘Evolution brings Ca 2+ and ATP together to control life and death’.