2. Academic Validation
  3. Arnicolide D induces endoplasmic reticulum stress-mediated oncosis via ATF4 and CHOP in hepatocellular carcinoma cells

Arnicolide D induces endoplasmic reticulum stress-mediated oncosis via ATF4 and CHOP in hepatocellular carcinoma cells

  • Cell Death Discov. 2024 Mar 12;10(1):134. doi: 10.1038/s41420-024-01911-w.
Yu-Shan Lin # 1,  Zhiwei Sun # 1,  Li-Sha Shen 2,  Rui-Hong Gong 3,  Jia-Wen Chen 1 4,  Yanfeng Xu 5,  Haiyang Yu 6,  Sibao Chen 7 8 9 10,  Guo-Qing Chen 11 12 13
Affiliations

Affiliations

  • 1 State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, 518057, China.
  • 2 Chongqing Academy of Chinese Materia Medica, Chongqing, 400065, China.
  • 3 Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, 999077, Hong Kong, China.
  • 4 Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, 100193, Beijing, China.
  • 5 Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai, 200071, China.
  • 6 Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, and State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
  • 7 State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, 518057, China. sibao.chen@polyu.edu.hk.
  • 8 Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, 999077, Hong Kong, China. sibao.chen@polyu.edu.hk.
  • 9 Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, 100193, Beijing, China. sibao.chen@polyu.edu.hk.
  • 10 Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hung Hom, 999077, Hong Kong, China. sibao.chen@polyu.edu.hk.
  • 11 State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, 518057, China. guoqing.chen@polyu.edu.hk.
  • 12 Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, 999077, Hong Kong, China. guoqing.chen@polyu.edu.hk.
  • 13 Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hung Hom, 999077, Hong Kong, China. guoqing.chen@polyu.edu.hk.
  • # Contributed equally.
PMID: 38472168 DOI: 10.1038/s41420-024-01911-w
Abstract

Endoplasmic reticulum (ER) stress can trigger various cell death mechanisms beyond Apoptosis, providing promise in Cancer treatment. Oncosis, characterized by cellular swelling and increased membrane permeability, represents a non-apoptotic form of cell death. In our study, we discovered that Arnicolide D (AD), a natural sesquiterpene lactone compound, induces ER stress-mediated oncosis in hepatocellular carcinoma (HCC) cells, and this process is Reactive Oxygen Species (ROS)-dependent. Furthermore, we identified the activation of the PERK-eIF2α-ATF4-CHOP pathway during ER stress as a pivotal factor in AD-induced oncosis. Notably, the protein synthesis inhibitor cycloheximide (CHX) was found to effectively reverse AD-induced oncosis, suggesting ATF4 and CHOP may hold crucial roles in the induction of oncosis by AD. These proteins play a vital part in promoting protein synthesis during ER stress, ultimately leading to cell death. Subsequent studies, in where we individually or simultaneously knocked down ATF4 and CHOP in HCC cells, provided further confirmation of their indispensable roles in AD-induced oncosis. Moreover, additional animal experiments not only substantiated AD's ability to inhibit HCC tumor growth but also solidified the essential role of ER stress-mediated and ROS-dependent oncosis in AD's therapeutic potential. In summary, our research findings strongly indicate that AD holds promise as a therapeutic agent for HCC by its ability to induce oncosis.

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