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Molecular and Cellular Biology

Abstract 1733: p62/sequestosome 1 regulates caspase-8 activation by the Bcl-2 antagonist ABT-263 to enable crosstalk between autophagy and apoptosis.

Shengbing Huang, Jae Myung Park, Chunrong Yu and Frank A. Sinicrope
Shengbing Huang
Mayo Clinic College of Medicine, Rochester, MN.
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Jae Myung Park
Mayo Clinic College of Medicine, Rochester, MN.
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Chunrong Yu
Mayo Clinic College of Medicine, Rochester, MN.
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Frank A. Sinicrope
Mayo Clinic College of Medicine, Rochester, MN.
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DOI: 10.1158/1538-7445.AM2013-1733 Published April 2013
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Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC

Abstract

Background: Autophagy and apoptosis regulate cancer cell viability in response to cytotoxic stress; however, the functional relationship between these processes is unclear. During autophagy, the multifunctional p62/sequestosome 1 protein shuttles ubiquitinated proteins to the lysosome. Previously, we found that ectopic p62 can promote chemotherapy-induced apoptosis. Since Bcl-2 can regulate both autophagy and apoptosis, we determined whether ABT-263-induced apoptosis is regulated by p62.

Methods: Human colorectal cancer cell lines (HCT116, DLD1) were incubated with ABT-263 (0-2 μM) and caspase cleavage (immunoblotting), caspase-8 activation (luminescence), apoptosis (annexin V labeling), and autophagy (localization of GFP-LC3 by confocal microscopy) were analyzed. Caspase-8 was suppressed by siRNA or using caspase-8-deficient Jurkat cells. P62 mutants were generated by site-directed mutagenesis. Caspase-8 self aggregation and colocalization with p62 were studied in cells with lentiviral mCherry-p62, transfected with a non-cleavable caspase-8 fused with fluorescent Venus proteins (BiFC).

Results: We demonstrate that ABT-263 induces autophagy and a caspase-8-mediated apoptosis, shown using caspase-8 siRNA or caspase-8-deficient cells. Regulation of this process by p62 was demonstrated by the ability of ectopic p62 expression to enhance apoptosis and caspase-8 activation that were disrupted by mutations at p62 functional domains. In contrast, p62 shRNA was shown to attenuate ABT-263-induced apoptosis. ABT-263 treatment enhanced binding between caspase-8 and p62, and triggered caspase-8 self aggregation that colocalized with p62, shown by Biomolecular Fluorescence Complementation (BiFC) assay using confocal microscopy. Consistent with ectopic p62, accumulation of p62 by the lysosomal autophagy inhibitors, chloroquine or bafilomycin A1, enhanced ABT-263-mediated caspase cleavage.

Conclusion: p62 can regulate caspase-8 self aggregation/activation by ABT-263 to enable crosstalk between autophagy and apoptosis.

Citation Format: Shengbing Huang, Jae Myung Park, Chunrong Yu, Frank A. Sinicrope. p62/sequestosome 1 regulates caspase-8 activation by the Bcl-2 antagonist ABT-263 to enable crosstalk between autophagy and apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1733. doi:10.1158/1538-7445.AM2013-1733

  • ©2013 American Association for Cancer Research
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Cancer Research: 73 (8 Supplement)
April 2013
Volume 73, Issue 8 Supplement
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Abstract 1733: p62/sequestosome 1 regulates caspase-8 activation by the Bcl-2 antagonist ABT-263 to enable crosstalk between autophagy and apoptosis.
Shengbing Huang, Jae Myung Park, Chunrong Yu and Frank A. Sinicrope
Cancer Res April 15 2013 (73) (8 Supplement) 1733; DOI: 10.1158/1538-7445.AM2013-1733

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Abstract 1733: p62/sequestosome 1 regulates caspase-8 activation by the Bcl-2 antagonist ABT-263 to enable crosstalk between autophagy and apoptosis.
Shengbing Huang, Jae Myung Park, Chunrong Yu and Frank A. Sinicrope
Cancer Res April 15 2013 (73) (8 Supplement) 1733; DOI: 10.1158/1538-7445.AM2013-1733
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