Repeated H2O2 exposure drives cell cycle progression in an in vitro model of ulcerative colitis. Issue 12 (9th October 2013)

• Record Type: Journal Article
• Authors: Poehlmann, Angela; Reissig, Kathrin; Schönfeld, Peter; Walluscheck, Diana; Schinlauer, Antje; Hartig, Roland; Lessel, Wiebke; Guenther, Thomas; Silver, Andrew; Roessner, Albert
• Is Part Of: Journal of cellular and molecular medicine. Volume 17:Issue 12(2013)
• Page Start: 1619
• Page End: 1631
• Publication Date: 2013-10-09
• 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.12150
• Languages: English
• ISSNs: 1582-1838

Abstract

<abstract abstract-type="main" id="jcmm12150-abs-0001"> <title>Abstract</title> <p>The production of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) drives tumourigenesis in ulcerative colitis (UC). Recently, we showed that H<sub>2</sub>O<sub>2</sub> activates DNA damage checkpoints in human colonic epithelial cells (HCEC) through c‐Jun <italic>N</italic>‐terminal Kinases (JNK) that induces p21<sup>WAF1</sup>. Moreover, caspases circumvented the G1/S and intra‐S checkpoints, and cells accumulated in G2/M. The latter observation raised the question of whether repeated H<sub>2</sub>O<sub>2</sub> exposures alter JNK activation, thereby promoting a direct passage of cells from G2/M arrest to driven cell cycle progression. Here, we report that increased proliferation of repeatedly H<sub>2</sub>O<sub>2</sub>‐exposed HCEC cells (C‐cell cultures) was associated with (<italic>i</italic>) increased phospho‐p46 JNK, (<italic>ii</italic>) decreased total JNK and phospho‐p54 JNK and (<italic>iii</italic>) p21<sup>WAF1</sup> down‐regulation. Altered JNK activation and p21<sup>WAF1</sup> down‐regulation were accompanied by defects in maintaining G2/M and mitotic spindle checkpoints through adaptation, as well as by apoptosis resistance following H<sub>2</sub>O<sub>2</sub> exposure. This may cause increased proliferation of C‐cell cultures, a defining initiating feature in the inflammation‐carcinoma pathway in UC. We further suggest that dysregulated JNK activation is attributed to a non‐apoptotic function of caspases, causing checkpoint adaptation in C‐cell cultures. Additionally, loss of cell‐contact inhibition and the overcoming of senescence, hallmarks of cancer, contributed to increased proliferation. Furthermore, there was evidence that p54 JNK inactivation is responsible for loss of cell‐contact inhibition. We present a cellular model of UC and suggest a sinusoidal pattern of proliferation, which is triggered by H<sub>2</sub>O<sub>2</sub>‐induced reactive oxygen species generation, involving an interplay between JNK activation/inactivation, p21<sup>WAF1</sup>, c‐Fos, c‐Jun/phospho‐c‐Jun, ATF2/phospho‐ATF2, β‐catenin/TCF4‐signalling, c‐Myc, CDK6 and Cyclin D2, leading to driven cell cycle progression.</p> </abstract>