KMID : 0624620220550110547
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BMB Reports 2022 Volume.55 No. 11 p.547 ~ p.552
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DN200434, an orally available inverse agonist of estrogen-related receptor ¥ã, induces ferroptosis in sorafenib-resistant hepatocellular carcinoma
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Kim Dong-Ho
Kim Mi-Jin Kim Na-Young Lee Seung-Hyeong Byun Jun-Kyu Yun Jae-Won Lee Jae-Bon Jin Jong-Hwa Kim Ji-Na Chin Jung-Wook Cho Sung-Jin Lee In-Kyu Choi Yeon-Kyung Park Keun-Gyu
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Abstract
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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 ¥ã (ERR¥ã) 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 ERR¥ã with DN200434, an orally available inverse agonist, can overcome resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenib-induced ferroptosis and showed significantly higher ERR¥ã 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.
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KEYWORD
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DN200434, ERR¥ã, Ferroptosis, Hepatocellular carcinoma, Sorafenib
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