Role of ATF3 for ER Stress-induced Sensitization of p53-deficient Human Colon Cancer Cells to TRAIL-mediated Apoptosis Through Upregulation of DR5 by Zerumbone and Celecoxib [Gene Regulation]

June 17th, 2014 by Edagawa, M., Kawauchi, J., Hirata, M., Goshima, H., Inoue, M., Okamoto, T., Murakami, A., Maehara, Y., Kitajima, S.

Death receptor 5 (DR5) is a death domain-containing transmembrane receptor that triggers cell death upon binding to its ligand TRAIL, and a combination of TRAIL and agents that increase the expression of DR5 is expected as a novel anti-cancer therapy. In this report, we demonstrate that stress response gene ATF3 was required for ER stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells. Both agents activated PERK-eIF2α kinases and induced the expression of ATF4-CHOP, which were remarkably suppressed by ROS scavengers. In the absence of ATF3, induction of DR5 mRNA and protein was significantly abrogated, and this was associated with reduced cell death by co-treatment of TRAIL with ZER or CCB. By contrast, exogenous expression of ATF3 caused more rapid and elevated expression of DR5, resulting in enhanced sensitivity to apoptotic cell death by TRAIL/ZER or TRAIL/CCB. Reporter assay demonstrated that at least two ATF/CRE motifs as well as CHOP motif at the proximal region of the human DR5 gene promoter were required for the ZER-induced DR5 gene transcription. Taken together, our results provide a novel insight into the role of ATF3 as an essential transcription factor for p53-independent DR5 induction upon both ZER and CCB, and this may represent a useful biomarker for TRAIL-based anti-cancer therapy.
  • Posted in Journal of Biological Chemistry, Publications
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