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

作者全名：Dong, Lixia; Luo, Li; Wang, Zihao; Lian, Shan; Wang, Mao; Wu, Xingyun; Fan, Jiawu; Zeng, Yan; Li, Sijia; Lv, Sinan; Yang, Yurong; Chen, Rong; Shen, Enhao; Yang, Wenyong; Li, Changlong; Wang, Kui

作者地址：[Dong, Lixia; Lian, Shan; Wang, Mao; Wu, Xingyun; Fan, Jiawu; Zeng, Yan; Li, Sijia; Lv, Sinan; Yang, Yurong; Chen, Rong; Shen, Enhao; Li, Changlong; Wang, Kui] Sichuan Univ, West China Hosp, West China Sch Basic Med Sci & Forens Med, State Key Lab Biotherapy, Chengdu 610041, Peoples R China; [Luo, Li] Sichuan Univ, West China Univ Hosp 2, Ctr Reprod Med, Dept Gynecol & Obstet, Chengdu 610041, Peoples R China; [Luo, Li] Sichuan Univ, Minist Educ, Key Lab Birth Defects & Related Dis Women & Childr, Chengdu 610041, Peoples R China; [Wang, Zihao] Sichuan Univ, West China Hosp, Colorectal Canc Ctr, Chengdu 610041, Peoples R China; [Yang, Wenyong] Chongqing Med Univ, Southwest Jiaotong Univ, Affiliated Hosp, Peoples Hosp Chengdu 3,Chengdu Hosp 2,Med Res Ctr,, Chengdu 610041, Peoples R China

通信作者：Li, CL; Wang, K (通讯作者)，Sichuan Univ, West China Hosp, West China Sch Basic Med Sci & Forens Med, State Key Lab Biotherapy, Chengdu 610041, Peoples R China.; Yang, WY (通讯作者)，Chongqing Med Univ, Southwest Jiaotong Univ, Affiliated Hosp, Peoples Hosp Chengdu 3,Chengdu Hosp 2,Med Res Ctr,, Chengdu 610041, Peoples R China.

来源：FREE RADICAL BIOLOGY AND MEDICINE

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001239609900001

JCR分区：Q1

影响因子：7.1

年份：2024

卷号：220

期号：　

开始页：111

结束页：124

文献类型：Article

关键词：Agrimol B; NDUFS1; Hepatocellular carcinoma; Autophagy; mROS; Sorafenib

摘要：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.

基金机构：Chinese NSFC [82373122, 82073081, 82172588, 82303238, 82002963]; Guangdong Basic and Applied Basic Research Foun [2019B030302012]

基金资助正文：This work was supported by the Chinese NSFC No. 82373122 (K.W.) , No. 82073081 (K.W.) , No. 82172588 (C.L.) , No. 82303238 (Y.Y.) , No. 82002963 (L.L.) ; Guangdong Basic and Applied Basic Research Foun- dation No. 2019B030302012 (K.W.) .