Non‐apoptotic function of caspases in a cellular model of hydrogen peroxide‐associated colitis

Journal of Cellular and Molecular Medicine

Angela Poehlmann¹  Kathrin Reissig¹  Andrea Just¹  Diana Walluscheck¹  Roland Hartig⁴  Antje Schinlauer¹  Wiebke Lessel¹  Thomas Guenther¹  Andrew Silver²  Pablo Steinberg³ 

[1] Department of Pathology, Otto-von-Guericke University, Magdeburg, Germany;Colorectal Cancer Genetics, Centre for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, UK;Institute of Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany;Department of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany

关键词: hydrogen peroxide‐associated colitis;    DNA‐damage checkpoints;    non‐apoptotic caspase function;    JNK‐dependent cell cycle arrests;    inflammation;    neoplastic transformation;    ATM degradation;    γ‐H2AX;   

DOI  :  10.1111/jcmm.12079

来源: Wiley

【 摘 要 】

Abstract

Oxidative stress, caused by reactive oxygen species (ROS), is a major contributor to inflammatory bowel disease (IBD)-associated neoplasia. We mimicked ROS exposure of the epithelium in IBD using non-tumour human colonic epithelial cells (HCEC) and hydrogen peroxide (H₂O₂). A population of HCEC survived H₂O₂-induced oxidative stress via JNK-dependent cell cycle arrests. Caspases, p21^WAF1 and γ-H2AX were identified as JNK-regulated proteins. Up-regulation of caspases was linked to cell survival and not, as expected, to apoptosis. Inhibition using the pan-caspase inhibitor Z-VAD-FMK caused up-regulation of γ-H2AX, a DNA-damage sensor, indicating its negative regulation via caspases. Cell cycle analysis revealed an accumulation of HCEC in the G₁-phase as first response to oxidative stress and increased S-phase population and then apoptosis as second response following caspase inhibition. Thus, caspases execute a non-apoptotic function by promoting cells through G₁- and S-phase by overriding the G₁/S- and intra-S checkpoints despite DNA-damage. This led to the accumulation of cells in the G₂/M-phase and decreased apoptosis. Caspases mediate survival of oxidatively damaged HCEC via γ-H2AX suppression, although its direct proteolytic inactivation was excluded. Conversely, we found that oxidative stress led to caspase-dependent proteolytic degradation of the DNA-damage checkpoint protein ATM that is upstream of γ-H2AX. As a consequence, undetected DNA-damage and increased proliferation were found in repeatedly H₂O₂-exposed HCEC. Such features have been associated with neoplastic transformation and appear here to be mediated by a non-apoptotic function of caspases. Overexpression of upstream p-JNK in active ulcerative colitis also suggests a potential importance of this pathway in vivo.

【 授权许可】

CC BY   
© 2013 The Authors. Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.