Caspase-8-mediated apoptosis induced by oxidative stress is independent of the intrinsic pathway and dependent on cathepsins

Baumgartner, Heidi K, Gerasimenko, Julia V, Thorne, Christopher, Ashurst, Louise H, Barrow, Stephanie L, Chvanov, Michael A, Gillies, Stuart, Criddle, David N, Tepikin, Alexei V, Petersen, Ole H, Sutton, Robert, Watson, Alastair J M ORCID: and Gerasimenko, Oleg V (2007) Caspase-8-mediated apoptosis induced by oxidative stress is independent of the intrinsic pathway and dependent on cathepsins. AJP: Gastrointestinal and Liver Physiology, 293 (1). G296-G307. ISSN 0193-1857

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Cell-death programs executed in the pancreas under pathological conditions remain largely undetermined, although the severity of experimental pancreatitis has been found to depend on the ratio of apoptosis to necrosis. We have defined mechanisms by which apoptosis is induced in pancreatic acinar cells by the oxidant stressor menadione. Real-time monitoring of initiator caspase activity showed that caspase-9 (66% of cells) and caspase-8 (15% of cells) were activated within 30 min of menadione administration, but no activation of caspase-2, -10, or -12 was detected. Interestingly, when caspase-9 activation was inhibited, activation of caspase-8 was increased. Half-maximum activation (t(0.5)) of caspase-9 occurred within approximately 2 min and was identified at or in close proximity to mitochondria, whereas t(0.5) for caspase-8 occurred within approximately 26 min of menadione application and was distributed homogeneously throughout cells. Caspase-9 but not caspase-8 activation was blocked completely by the calcium chelator BAPTA or bongkrekic acid, an inhibitor of the mitochondrial permeability transition pore. In contrast, caspase-8 but not caspase-9 activation was blocked by the destruction of lysosomes (preincubation with Gly-Phe beta-naphthylamide, a cathepsin C substrate), loss of lysosomal acidity (bafilomycin A1), or inhibition of cathepsin L or D. Using pepstatin A-BODIPY FL conjugate, we confirmed translocation of cathepsin D out of lysosomes in response to menadione. We conclude that the oxidative stressor menadione induces two independent apoptotic pathways within pancreatic acinar cells: the classical mitochondrial calcium-dependent pathway that is initiated rapidly in the majority of cells, and a slower, caspase-8-mediated pathway that depends on the lysosomal activities of cathepsins and is used when the caspase-9 pathway is disabled.

Item Type: Article
Uncontrolled Keywords: animals,apoptosis,bongkrekic acid,calcium,caspase 8,caspase 9,cathepsin d,cathepsins,egtazic acid,enzyme activation,lysosomes,male,mice,models, biological,oxidative stress,pancreas,vitamin k 3
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Depositing User: Rhiannon Harvey
Date Deposited: 01 Apr 2011 09:17
Last Modified: 20 Aug 2023 00:30
DOI: 10.1152/ajpgi.00103.2007

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