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

Peng, Shuang, Gerasimenko, Julia V. ORCID: https://orcid.org/0000-0002-2262-2543, Tsugorka, Tatiana, Gryshchenko, Oleksiey, Samarasinghe, Sujith, Petersen, Ole H. ORCID: https://orcid.org/0000-0002-6998-0380 and Gerasimenko, Oleg V. ORCID: https://orcid.org/0000-0003-2573-8258 2016. Calcium and adenosine triphosphate control of cellular pathology: asparaginase-induced pancreatitis elicited via protease-activated receptor 2. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 371 (1700) , 20150423. 10.1098/rstb.2015.0423

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Abstract

Exocytotic secretion of digestive enzymes from pancreatic acinar cells is elicited by physiological cytosolic Ca2+ 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 Ca2+ elevations decrease ATP levels and cause necrosis, leading to the disease acute pancreatitis (AP). Toxic Ca2+ 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 Ca2+ release followed by Ca2+ entry and also substantially reduced Ca2+ extrusion because of decreased intracellular ATP levels. The toxic Ca2+ signals caused extensive necrosis. The asparaginase-induced pathology depended on protease-activated receptor 2 and its inhibition prevented the toxic Ca2+ signals and necrosis. We tested the effects of inhibiting the Ca2+ release-activated Ca2+ entry by the Ca2+ channel inhibitor GSK-7975A. This markedly reduced asparaginase-induced Ca2+ entry and also protected effectively against the development of necrosis.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Additional Information:	Published by the Royal Society under the terms of the Creative Commons Attribution License.
Publisher:	Royal Society, The
ISSN:	0080-4622
Funders:	MRC
Date of First Compliant Deposit:	17 May 2016
Date of Acceptance:	20 April 2016
Last Modified:	06 May 2023 05:44
URI:	https://orca.cardiff.ac.uk/id/eprint/90961

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