Effect of pristimerin on apoptosis through activation of ROS/ endoplasmic reticulum (ER) stress-mediated noxa in colorectal cancer

  • Phytomedicine. 2021 Jan;80:153399. doi: 10.1016/j.phymed.2020.153399.
Qun Zhao  1 ,  Yun Bi  2 ,  Jian Guo  2 ,  Yingxiang Liu  2 ,  Jing Zhong  3 ,  Yongqiang Liu  4 ,  Longrui Pan  2 ,  Yang Guo  2 ,  Yan Tan  2 ,  Xianjun Yu  5
Affiliations
  • 1. Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China; State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
  • 2. Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China.
  • 3. Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China; Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, China.
  • 4. Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
  • 5. Laboratory of Inflammation and Molecular Pharmacology, School of Basic Medical Sciences & Biomedical Research Institute, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan 442000, China. Electronic address: [email protected].
PMID: 33202325 DOI: 10.1016/j.phymed.2020.153399
Abstract

Background: Pristimerin, a natural quinonemethid triterpenoid found in different spp. of Celastraceae and Hippocrateaceae families, has been reported to exhibit potent antitumor activities against colorectal Cancer (CRC). However, the mechanisms underlying pristimerin-induced Apoptosis in CRC is not clear.

Purpose: This study aimed to investigate the mechanisms of pristimerin-induced Apoptosis against CRC in vitro and in vivo.

Methods: Cell viability and cell Apoptosis analyses were conducted to assess the effects of pristimerin on CRC. Western blotting was performed to detect the expression of proteins affected by pristimerin in vitro and in vivo. HCT116 colon Cancer xenografts and APCmin/+ mouse models were used to evaluate the anti-CRC effect of pristimerin in vivo.

Results: Our data showed that pristimerin induced Apoptosis by regulating proapoptotic proteins of which Noxa showed higher expression. Pristimerin triggered Reactive Oxygen Species (ROS)-mediated endoplasmic reticulum (ER) stress signaling activation. Pristimerin significantly elevated the expression of ER stress-related proteins, resulting in activation of the IRE1α and c-Jun N-terminal kinase (JNK) signal pathway through the formation of the IRE1α-TRAF2-ASK1 complex. Pristimerin exhibited apoptosis-inducing activities in HCT116 colon Cancer xenografts and APCmin/+ mice.

Conclusion: Both in vitro and in vivo data demonstrated that pristimerin induced Noxa expression and Apoptosis through activation of the ROS/ER stress/JNK axis in CRC. Thus, pristimerin may be a promising antitumor agent for CRC.

Keywords
Apoptosis; Colorectal cancer; ER stress; Noxa; Pristimerin; ROS.
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