Sorafenib induces mitochondrial dysfunction and exhibits synergistic effect with cysteine depletion by promoting HCC cells ferroptosis
Sorafenib induces mitochondrial dysfunction and exhibits synergistic effect with cysteine depletion by promoting HCC cells ferroptosis
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DOI：
10.1016/j.bbrc.2020.10.083
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发表时间：
2021-01-01
影响因子：
3.1
通讯作者：
Ren, Xueying
中科院分区：
文献类型：
--
作者：
Li, Yanchun;Xia, Jun;Ren, Xueying
肝细胞癌（HCC）是全世界最常见的恶性肿瘤之一。 HCC 的预后仍然很差。目前，索拉非尼是晚期肝癌的一线药物。尽管索拉非尼涉及几个已确定的癌症相关蛋白激酶靶标的作用机制已得到充分表征，但其潜在的分子机制仍不清楚。在这里，我们发现索拉非尼以剂量依赖性方式抑制 HCC 细胞的活力、增殖和迁移。索拉非尼处理 HCC 细胞破坏了线粒体形态，伴随着氧化磷酸化活性降低、线粒体膜电位崩溃和 ATP 合成减少，最终因铁死亡而导致细胞死亡。谷胱甘肽 (GSH) 的药理利用可挽救索拉非尼诱导的铁死亡，消除细胞线粒体活性氧 (ROS) 和脂质过氧化物的积累。通过半胱氨酸剥夺或半胱氨酸酶抑制导致的 GSH 消耗加剧了索拉非尼诱导的铁死亡和脂质过氧化物的产生，并增强了氧化应激和线粒体 ROS 积累。总的来说，这些发现表明，半胱氨酸的消耗与索拉非尼协同作用，使 HCC 细胞容易发生铁死亡，这为晚期 HCC 提供了新的治疗组合的潜在价值。 (C) 2020 Elsevier Inc. 保留所有权利。
Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide. The prognosis of HCC remains poor. Currently, sorafenib is the first-line drug for advanced HCC. Although sorafenib's mechanism of action involving several established cancer-related protein kinase targets is well-characterized, the underlying molecular mechanism is still unclear. Here, we found that sorafenib inhibited viability, proliferation, and migration of HCC cells in a dose-dependent manner. Sorafenib treatment of HCC cells destroyed mitochondrial morphology, accompanied by decreased activity of oxidative phosphorylation, collapse of mitochondrial membrane potential, and reduced synthesis of ATP, with consequent cell death due to ferroptosis. Pharmacological utilization of glutathione (GSH) rescued the sorafenib-induced ferroptosis, eliminated the accumulation of cellular mitochondrial reactive oxygen species (ROS), and lipid peroxide. GSH depletion through cysteine deprivation or cysteinase inhibition exacerbated sorafenib-induced ferroptotic cell death and lipid peroxides generation, and enhanced oxidative stress and mitochondrial ROS accumulation. Collectively, these findings indicate that depletion of cysteine acts synergistically with sorafenib and renders HCC cells vulnerable to ferroptosis, presenting the potential value of new therapeutic combinations for advanced HCC. (C) 2020 Elsevier Inc. All rights reserved.