These authors contributed equally to this study.
ATF2 knockdown reinforces oxidative stress-induced apoptosis in TE7 cancer cells
Article first published online: 25 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 8, pages 976–988, August 2013
How to Cite
Walluscheck, D., Poehlmann, A., Hartig, R., Lendeckel, U., Schönfeld, P., Hotz-Wagenblatt, A., Reissig, K., Bajbouj, K., Roessner, A. and Schneider-Stock, R. (2013), ATF2 knockdown reinforces oxidative stress-induced apoptosis in TE7 cancer cells. Journal of Cellular and Molecular Medicine, 17: 976–988. doi: 10.1111/jcmm.12071
- Issue published online: 29 AUG 2013
- Article first published online: 25 JUN 2013
- Manuscript Accepted: 1 APR 2013
- Manuscript Received: 27 OCT 2012
- oxidative stress-induced DNA damage;
- cell cycle arrest;
- ATF2 knockdown;
- increase in apoptosis sensitivities;
- combined treatment;
Cancer cells showing low apoptotic effects following oxidative stress-induced DNA damage are mainly affected by growth arrest. Thus, recent studies focus on improving anti-cancer therapies by increasing apoptosis sensitivity. We aimed at identifying a universal molecule as potential target to enhance oxidative stress-based anti-cancer therapy through a switch from cell cycle arrest to apoptosis. A cDNA microarray was performed with hydrogen peroxide-treated oesophageal squamous epithelial cancer cells TE7. This cell line showed checkpoint activation via p21WAF1, but low apoptotic response following DNA damage. The potential target molecule was chosen depended on the following demands: it should regulate DNA damage response, cell cycle and apoptosis. As the transcription factor ATF2 is implicated in all these processes, we focused on this protein. We investigated checkpoint activation via ATF2. Indeed, ATF2 knockdown revealed ATF2-triggered p21WAF1 protein expression, suggesting p21WAF1 transactivation through ATF2. Using chromatin immunoprecipitation (ChIP), we identified a hitherto unknown ATF2-binding sequence in the p21WAF1 promoter. p-ATF2 was found to interact with p-c-Jun, creating the AP-1 complex. Moreover, ATF2 knockdown led to c-Jun downregulation. This suggests ATF2-driven induction of c-Jun expression, thereby enhancing ATF2 transcriptional activity via c-Jun-ATF2 heterodimerization. Notably, downregulation of ATF2 caused a switch from cell cycle arrest to reinforced apoptosis, presumably via p21WAF1 downregulation, confirming the importance of ATF2 in the establishment of cell cycle arrest. 1-Chloro-2,4-dinitrobenzene also led to ATF2-dependent G2/M arrest, suggesting that this is a general feature induced by oxidative stress. As ATF2 knockdown also increased apoptosis, we propose ATF2 as a target for combined oxidative stress-based anti-cancer therapies.