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

Baumgartner, H. K., Gerasimenko, Julia Vladimirovna ORCID:, Thorne, C., Ashurst, L. H., Barrow, S. L., Chvanov, M. A., Gillies, S., Criddle, D. N., Tepikin, A. V., Petersen, Ole Holger ORCID:, Sutton, R., Watson, A. J. M. and Gerasimenko, Oleg Vsevolodovich ORCID: 2007. Caspase-8-mediated apoptosis induced by oxidative stress is independent of the intrinsic pathway and dependent on cathepsins. American Journal of Physiology-Gastrointestinal and Liver Physiology 293 (1) , G296-G307. 10.1152/ajpgi.00103.2007

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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 (t0.5) of caspase-9 occurred within ∼2 min and was identified at or in close proximity to mitochondria, whereas t0.5 for caspase-8 occurred within ∼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 β-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
Date Type: Publication
Status: Published
Schools: Biosciences
Systems Immunity Research Institute (SIURI)
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0193-1857
Date of Acceptance: 5 April 2007
Last Modified: 25 Oct 2022 10:10

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