Non‐apoptotic function of caspases in a cellular model of hydrogen peroxide‐associated colitis. Issue 7 (7th June 2013)

• Record Type: Journal Article
• Authors: Poehlmann, Angela; Reissig, Kathrin; Just, Andrea; Walluscheck, Diana; Hartig, Roland; Schinlauer, Antje; Lessel, Wiebke; Guenther, Thomas; Silver, Andrew; Steinberg, Pablo; Roessner, Albert
• Is Part Of: Journal of cellular and molecular medicine. Volume 17:Issue 7(2013)
• Page Start: 901
• Page End: 913
• Publication Date: 2013-06-07
• Subjects: Cytology; Medicine; Molecular Biology; Cytologie -- Périodiques; Médecine -- Périodiques; Biologie moléculaire -- Périodiques; Cytology -- Periodicals; Medicine -- Periodicals; Molecular biology -- Periodicals; 611.01805
• DOI: 10.1111/jcmm.12079
• Languages: English
• ISSNs: 1582-1838

Abstract

<abstract abstract-type="main" id="jcmm12079-abs-0001"> <title>Abstract</title> <p>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 (H<sub>2</sub>O<sub>2</sub>). A population of HCEC survived H<sub>2</sub>O<sub>2</sub>‐induced oxidative stress <italic>via </italic>JNK‐dependent cell cycle arrests. Caspases, p21<sup>WAF1</sup> 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 <italic>via</italic> caspases. Cell cycle analysis revealed an accumulation of HCEC in the G<sub>1</sub>‐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 G<sub>1</sub>‐ and S‐phase by overriding the G<sub>1</sub>/S‐ and intra‐S checkpoints despite DNA‐damage. This led to the accumulation of cells in the G<sub>2</sub>/M‐phase and decreased apoptosis. Caspases mediate survival of oxidatively damaged HCEC <italic>via</italic> 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 H<sub>2</sub>O<sub>2</sub>‐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 <italic>in vivo</italic>.</p> </abstract>