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Biochem Biophys Res Commun. 2014 Mar 7;445(2):320-6. doi: 10.1016/j.bbrc.2014.01.184. Epub 2014 Feb 12.

Role of ATF3 in synergistic cancer cell killing by a combination of HDAC inhibitors and agonistic anti-DR5 antibody through ER stress in human colon cancer cells.

Author information

1
Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China; Department of Thyroid Surgery, First Hospital of Jilin University, Changchun, Jilin 130021, China.
2
Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
3
Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
4
Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China. Electronic address: liuzh@jlu.edu.cn.
5
Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan. Electronic address: kita.bgen@mri.tmd.ac.jp.

Abstract

Histone deacetylase inhibitors (HDACIs) are promising agents for cancer therapy. However, the mechanism(s) responsible for the efficacy of HDACIs have not yet to be fully elucidated. Death receptor 5 (DR5) is a transmembrane receptor containing death domain that triggers cell death upon binding to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) or agonistic anti-DR5 monoclonal antibody, and the combination of TRAIL/agonistic anti-DR5 monoclonal antibody and agents that increase the expression of DR5 is expected as a novel anticancer therapeutic strategy. Here we report that six different HDACIs activated endoplasmic reticulum (ER) stress sensor PERK and eIF2α and induced the ATF4/ATF3/CHOP pathway in p53-deficient human colon cancer cells. This resulted in an increased expression of DR5 on the cell surface and sensitized cells to apoptosis by agonistic anti-DR5 monoclonal antibody. Stress response gene ATF3 was required for efficient DR5 induction by HDACIs, and DR5 reporter assay showed that ATF3 play crucial role for the HDACIs-induced activation of DR5 gene transcription. These provide important mechanistic insight into how HDACIs exhibit pro-apoptotic activity in clinical anti-cancer treatments when they are used in combination with other therapeutic strategies.

KEYWORDS:

ATF3; Agonistic anti-DR5 antibody; DR5; ER stress; HDACI

PMID:
24530917
DOI:
10.1016/j.bbrc.2014.01.184
[Indexed for MEDLINE]

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