2. Academic Validation
  3. Targeted degradation of NDUFS1 by agrimol B promotes mitochondrial ROS accumulation and cytotoxic autophagy arrest in hepatocellular carcinoma

Targeted degradation of NDUFS1 by agrimol B promotes mitochondrial ROS accumulation and cytotoxic autophagy arrest in hepatocellular carcinoma

  • Free Radic Biol Med. 2024 Apr 30:220:111-124. doi: 10.1016/j.freeradbiomed.2024.04.242.
Lixia Dong 1,  Li Luo 2,  Zihao Wang 3,  Shan Lian 1,  Mao Wang 1,  Xingyun Wu 1,  Jiawu Fan 1,  Yan Zeng 1,  Sijia Li 1,  Sinan Lv 1,  Yurong Yang 1,  Rong Chen 1,  Enhao Shen 1,  Wenyong Yang 4,  Changlong Li 5,  Kui Wang 6
Affiliations

Affiliations

  • 1 West China School of Basic Medical Sciences & Forensic Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
  • 2 Center for Reproductive Medicine, Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, PR China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, PR China.
  • 3 Colorectal Cancer Center, West China Hospital, Sichuan University, 610041, PR China.
  • 4 Department of Neurosurgery, Medical Research Center, the Third People's Hospital of Chengdu, the Affiliated Hospital of Southwest Jiaotong University, the Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, 610041, PR China. Electronic address: ywenyong@hotmail.com.
  • 5 West China School of Basic Medical Sciences & Forensic Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China. Electronic address: changlongli@scu.edu.cn.
  • 6 West China School of Basic Medical Sciences & Forensic Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China. Electronic address: kuiwang@scu.edu.cn.
PMID: 38697493 DOI: 10.1016/j.freeradbiomed.2024.04.242
Abstract

Hepatocellular carcinoma (HCC) is a global public health problem with increased morbidity and mortality. Agrimol B, a natural polyphenol, has been proved to be a potential Anticancer drug. Our recent report showed a favorable Anticancer effect of agrimol B in HCC, however, the mechanism of action remains unclear. Here, we found agrimol B inhibits the growth and proliferation of HCC cells in vitro as well as in an HCC patient-derived xenograft (PDX) model. Notably, agrimol B drives Autophagy initiation and blocks autophagosome-lysosome fusion, resulting in autophagosome accumulation and Autophagy arrest in HCC cells. Mechanistically, agrimol B downregulates the protein level of NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1) through Caspase 3-mediated degradation, leading to mitochondrial Reactive Oxygen Species (mROS) accumulation and Autophagy arrest. NDUFS1 overexpression partially restores mROS overproduction, autophagosome accumulation, and growth inhibition induced by agrimol B, suggesting a cytotoxic role of agrimol B-induced Autophagy arrest in HCC cells. Notably, agrimol B significantly enhances the sensitivity of HCC cells to sorafenib in vitro and in vivo. In conclusion, our study uncovers the Anticancer mechanism of agrimol B in HCC involving the regulation of oxidative stress and Autophagy, and suggests agrimol B as a potential therapeutic drug for HCC treatment.

Keywords

Agrimol B; Autophagy; Hepatocellular carcinoma; NDUFS1; Sorafenib; mROS.

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