<br>agrimol B 靶向降解 NDUFS1 促进肝细胞癌中线粒体 ROS 积累和细胞毒性自噬抑制,Free Radical Biology and Medicine

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agrimol B 靶向降解 NDUFS1 促进肝细胞癌中线粒体 ROS 积累和细胞毒性自噬抑制
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2024-04-30 , 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 ₁ , Kui Wang ₁

Affiliation

肝细胞癌（HCC）是一个全球性的公共卫生问题，发病率和死亡率不断增加。 Agrimol B 是一种天然多酚，已被证明是一种潜在的抗癌药物。我们最近的报告显示了 agrimol B 在 HCC 中具有良好的抗癌作用，但作用机制仍不清楚。在这里，我们发现 agrimol B 抑制 HCC 细胞以及 HCC 患者来源的异种移植 (PDX) 模型的生长和增殖。值得注意的是，agrimol B 驱动自噬启动并阻断自噬体-溶酶体融合，导致 HCC 细胞中自噬体积累和自噬停滞。从机制上讲，agrimol B 通过 caspase 3 介导的降解下调 NADH：泛醌氧化还原酶核心亚基 S1 (NDUFS1) 的蛋白质水平，导致线粒体活性氧 (mROS) 积累和自噬停滞。 NDUFS1 过表达部分恢复了 agrimol B 诱导的 mROS 过量产生、自噬体积累和生长抑制，表明 agrimol B 诱导的 HCC 细胞自噬停滞具有细胞毒作用。值得注意的是，agrimol B 显着增强 HCC 细胞对索拉非尼和的敏感性。总之，我们的研究揭示了仙鹤醇 B 在 HCC 中涉及氧化应激和自噬调节的抗癌机制，并表明仙鹤醇 B 作为 HCC 治疗的潜在治疗药物。

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

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 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 and . 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.

更新日期：2024-04-30

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