These authors contributed equally.
Non-apoptotic function of caspases in a cellular model of hydrogen peroxide-associated colitis
Version of Record online: 7 JUN 2013
© 2013 The Authors. Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Journal of Cellular and Molecular Medicine
Volume 17, Issue 7, pages 901–913, July 2013
How to Cite
Poehlmann, A., Reissig, K., Just, A., Walluscheck, D., Hartig, R., Schinlauer, A., Lessel, W., Guenther, T., Silver, A., Steinberg, P. and Roessner, A. (2013), Non-apoptotic function of caspases in a cellular model of hydrogen peroxide-associated colitis. Journal of Cellular and Molecular Medicine, 17: 901–913. doi: 10.1111/jcmm.12079
- Issue online: 24 JUL 2013
- Version of Record online: 7 JUN 2013
- Manuscript Accepted: 15 APR 2013
- Manuscript Received: 3 AUG 2012
- hydrogen peroxide-associated colitis;
- DNA-damage checkpoints;
- non-apoptotic caspase function;
- JNK-dependent cell cycle arrests;
- neoplastic transformation;
- ATM degradation;
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, p21WAF1 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.