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Title: Prodigiosin activates endoplasmic reticulum stress cell death pathway in human breast carcinoma cell lines

Abstract

Prodigiosin is a bacterial tripyrrole pigment with potent cytotoxicity against diverse human cancer cell lines. Endoplasmic reticulum (ER) stress is initiated by accumulation of unfolded or misfolded proteins in the ER lumen and may induce cell death when irremediable. In this study, the role of ER stress in prodigiosin-induced cytotoxicity was elucidated for the first time. Comparable to the ER stress inducer thapsigargin, prodigiosin up-regulated signature ER stress markers GRP78 and CHOP in addition to activating the IRE1, PERK and ATF6 branches of the unfolded protein response (UPR) in multiple human breast carcinoma cell lines, confirming prodigiosin as an ER stress inducer. Prodigiosin transcriptionally up-regulated CHOP, as evidenced by its promoting effect on the CHOP promoter activity. Of note, knockdown of CHOP effectively lowered prodigiosin's capacity to evoke PARP cleavage, reduce cell viability and suppress colony formation, highlighting an essential role of CHOP in prodigiosin-induced cytotoxic ER stress response. In addition, prodigiosin down-regulated BCL2 in a CHOP-dependent manner. Importantly, restoration of BCL2 expression blocked prodigiosin-induced PARP cleavage and greatly enhanced the survival of prodigiosin-treated cells, suggesting that CHOP-dependent BCL2 suppression mediates prodigiosin-elicited cell death. Moreover, pharmacological inhibition of JNK by SP600125 or dominant-negative blockade of PERK-mediated eIF2α phosphorylation impaired prodigiosin-inducedmore » CHOP up-regulation and PARP cleavage. Collectively, these results identified ER stress-mediated cell death as a mode-of-action of prodigiosin's tumoricidal effect. Mechanistically, prodigiosin engages the IRE1–JNK and PERK–eIF2α branches of the UPR signaling to up-regulate CHOP, which in turn mediates BCL2 suppression to induce cell death. Highlights: ► Prodigiosin is a bacterial tripyrrole pigment with potent anticancer effect. ► Prodigiosin is herein identified as an endoplasmic reticulum (ER) stress inducer. ► Prodigiosin-induced cytotoxicity involves ER stress-mediated cell death. ► Prodigiosin transcriptionally induces CHOP to suppress BCL2 for evoking cell death. ► Prodigiosin engages the IRE1–JNK and PERK–eIF2α pathways to up-regulate CHOP.« less

Authors:
 [1];  [1];  [2];  [3];  [2];  [1];  [4];  [1];  [1];  [2];  [2]
  1. Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China)
  2. (China)
  3. Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan (China)
  4. Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan (China)
Publication Date:
OSTI Identifier:
22216003
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 265; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; BIOLOGICAL RECOVERY; BIOLOGICAL STRESS; CARCINOMAS; CLEAVAGE; COLONY FORMATION; ENDOPLASMIC RETICULUM; INHIBITION; MAMMARY GLANDS; PHOSPHORYLATION; PIGMENTS; PROMOTERS; PROTEINS; TOXICITY

Citation Formats

Pan, Mu-Yun, Shen, Yuh-Chiang, National Research Institute of Chinese Medicine, Taipei, Taiwan, Lu, Chien-Hsing, Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan, Yang, Shu-Yi, Ho, Tsing-Fen, Peng, Yu-Ta, Chang, Chia-Che, E-mail: chia_che@dragon.nchu.edu.tw, Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, and Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan. Prodigiosin activates endoplasmic reticulum stress cell death pathway in human breast carcinoma cell lines. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.08.034.
Pan, Mu-Yun, Shen, Yuh-Chiang, National Research Institute of Chinese Medicine, Taipei, Taiwan, Lu, Chien-Hsing, Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan, Yang, Shu-Yi, Ho, Tsing-Fen, Peng, Yu-Ta, Chang, Chia-Che, E-mail: chia_che@dragon.nchu.edu.tw, Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, & Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan. Prodigiosin activates endoplasmic reticulum stress cell death pathway in human breast carcinoma cell lines. United States. doi:10.1016/J.TAAP.2012.08.034.
Pan, Mu-Yun, Shen, Yuh-Chiang, National Research Institute of Chinese Medicine, Taipei, Taiwan, Lu, Chien-Hsing, Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan, Yang, Shu-Yi, Ho, Tsing-Fen, Peng, Yu-Ta, Chang, Chia-Che, E-mail: chia_che@dragon.nchu.edu.tw, Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, and Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan. Sat . "Prodigiosin activates endoplasmic reticulum stress cell death pathway in human breast carcinoma cell lines". United States. doi:10.1016/J.TAAP.2012.08.034.
@article{osti_22216003,
title = {Prodigiosin activates endoplasmic reticulum stress cell death pathway in human breast carcinoma cell lines},
author = {Pan, Mu-Yun and Shen, Yuh-Chiang and National Research Institute of Chinese Medicine, Taipei, Taiwan and Lu, Chien-Hsing and Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan and Yang, Shu-Yi and Ho, Tsing-Fen and Peng, Yu-Ta and Chang, Chia-Che, E-mail: chia_che@dragon.nchu.edu.tw and Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan and Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan},
abstractNote = {Prodigiosin is a bacterial tripyrrole pigment with potent cytotoxicity against diverse human cancer cell lines. Endoplasmic reticulum (ER) stress is initiated by accumulation of unfolded or misfolded proteins in the ER lumen and may induce cell death when irremediable. In this study, the role of ER stress in prodigiosin-induced cytotoxicity was elucidated for the first time. Comparable to the ER stress inducer thapsigargin, prodigiosin up-regulated signature ER stress markers GRP78 and CHOP in addition to activating the IRE1, PERK and ATF6 branches of the unfolded protein response (UPR) in multiple human breast carcinoma cell lines, confirming prodigiosin as an ER stress inducer. Prodigiosin transcriptionally up-regulated CHOP, as evidenced by its promoting effect on the CHOP promoter activity. Of note, knockdown of CHOP effectively lowered prodigiosin's capacity to evoke PARP cleavage, reduce cell viability and suppress colony formation, highlighting an essential role of CHOP in prodigiosin-induced cytotoxic ER stress response. In addition, prodigiosin down-regulated BCL2 in a CHOP-dependent manner. Importantly, restoration of BCL2 expression blocked prodigiosin-induced PARP cleavage and greatly enhanced the survival of prodigiosin-treated cells, suggesting that CHOP-dependent BCL2 suppression mediates prodigiosin-elicited cell death. Moreover, pharmacological inhibition of JNK by SP600125 or dominant-negative blockade of PERK-mediated eIF2α phosphorylation impaired prodigiosin-induced CHOP up-regulation and PARP cleavage. Collectively, these results identified ER stress-mediated cell death as a mode-of-action of prodigiosin's tumoricidal effect. Mechanistically, prodigiosin engages the IRE1–JNK and PERK–eIF2α branches of the UPR signaling to up-regulate CHOP, which in turn mediates BCL2 suppression to induce cell death. Highlights: ► Prodigiosin is a bacterial tripyrrole pigment with potent anticancer effect. ► Prodigiosin is herein identified as an endoplasmic reticulum (ER) stress inducer. ► Prodigiosin-induced cytotoxicity involves ER stress-mediated cell death. ► Prodigiosin transcriptionally induces CHOP to suppress BCL2 for evoking cell death. ► Prodigiosin engages the IRE1–JNK and PERK–eIF2α pathways to up-regulate CHOP.},
doi = {10.1016/J.TAAP.2012.08.034},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 265,
place = {United States},
year = {Sat Dec 15 00:00:00 EST 2012},
month = {Sat Dec 15 00:00:00 EST 2012}
}