Department of Biomedical Science, Kyungpook National University, Daegu 41566, Korea.
Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566; Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea.
BMB Rep. 2022 Nov;55(11):547-552. doi: 10.5483/BMBRep.2022.55.11.089.
Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, induces ferroptosis in hepatocellular carcinoma (HCC) cells. Several pathways that mitigate sorafenib-induced ferroptosis confer drug resistance; thus strategies that enhance ferroptosis increase sorafenib efficacy. Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is upregulated in human HCC tissues and plays a role in cancer cell proliferation. The aim of this study was to determine whether inhibition of ERRγ with DN200434, an orally available inverse agonist, can overcome resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenibinduced ferroptosis and showed significantly higher ERRγ levels than sorafenib-sensitive HCC cells. DN200434 induced lipid peroxidation and ferroptosis in sorafenib-resistant HCC cells. Mechanistically, DN200434 increased mitochondrial ROS generation by reducing glutathione/glutathione disulfide levels, which subsequently reduced mTOR activity and GPX4 levels. DN200434 induced amplification of the antitumor effects of sorafenib was confirmed in a tumor xenograft model. The present results indicate that DN200434 may be a novel therapeutic strategy to re-sensitize HCC cells to sorafenib. [BMB Reports 2022; 55(11): 547-552].
索拉非尼最初被鉴定为多种致癌激酶的抑制剂，可诱导肝细胞癌 (HCC) 细胞发生铁死亡。减轻索拉非尼诱导的铁死亡的几种途径赋予了药物耐药性；因此，增强铁死亡的策略可以提高索拉非尼的疗效。孤儿核受体雌激素相关受体 γ (ERRγ) 在人 HCC 组织中上调，并在癌细胞增殖中发挥作用。本研究旨在确定用口服可用的反向激动剂 DN200434 抑制 ERRγ 是否可以通过诱导铁死亡来克服对索拉非尼的耐药性。对索拉非尼耐药的 HCC 细胞对索拉非尼诱导的铁死亡的敏感性较低，并且 ERRγ 水平明显高于对索拉非尼敏感的 HCC 细胞。DN200434 在索拉非尼耐药 HCC 细胞中诱导脂质过氧化和铁死亡。从机制上讲，DN200434 通过降低谷胱甘肽/谷胱甘肽二硫化物水平来增加线粒体 ROS 的产生，从而降低 mTOR 活性和 GPX4 水平。在肿瘤异种移植模型中证实，DN200434 诱导的索拉非尼抗肿瘤作用的放大。这些结果表明，DN200434 可能是一种重新使 HCC 细胞对索拉非尼敏感的新的治疗策略。[BMB 报告 2022；55(11): 547-552]。
