DN200434, an orally available inverse agonist of estrogen-related receptor γ, induces ferroptosis in sorafenib-resistant hepatocellular carcinoma
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Sorafenib, originally identified as an inhibitor of multiple oncogenickinases, induces ferroptosis in hepatocellular carcinoma(HCC) cells. Several pathways that mitigate sorafenib-inducedferroptosis confer drug resistance; thus strategies that enhanceferroptosis increase sorafenib efficacy. Orphan nuclear receptorestrogen-related receptor γ (ERRγ) is upregulated in humanHCC tissues and plays a role in cancer cell proliferation. Theaim of this study was to determine whether inhibition of ERRγwith DN200434, an orally available inverse agonist, can overcomeresistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenibinducedferroptosis and showed significantly higher ERRγ levelsthan sorafenib-sensitive HCC cells. DN200434 induced lipidperoxidation and ferroptosis in sorafenib-resistant HCC cells. Mechanistically,DN200434 increased mitochondrial ROS generationby reducing glutathione/glutathione disulfide levels, which subsequentlyreduced mTOR activity and GPX4 levels. DN200434induced amplification of the antitumor effects of sorafenib wasconfirmed in a tumor xenograft model. The present results indicatethat DN200434 may be a novel therapeutic strategy tore-sensitize HCC cells to sorafenib.
Abstract
Sorafenib, originally identified as an inhibitor of multiple oncogenickinases, induces ferroptosis in hepatocellular carcinoma(HCC) cells. Several pathways that mitigate sorafenib-inducedferroptosis confer drug resistance; thus strategies that enhanceferroptosis increase sorafenib efficacy. Orphan nuclear receptorestrogen-related receptor γ (ERRγ) is upregulated in humanHCC tissues and plays a role in cancer cell proliferation. Theaim of this study was to determine whether inhibition of ERRγwith DN200434, an orally available inverse agonist, can overcomeresistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenibinducedferroptosis and showed significantly higher ERRγ levelsthan sorafenib-sensitive HCC cells. DN200434 induced lipidperoxidation and ferroptosis in sorafenib-resistant HCC cells. Mechanistically,DN200434 increased mitochondrial ROS generationby reducing glutathione/glutathione disulfide levels, which subsequentlyreduced mTOR activity and GPX4 levels. DN200434induced amplification of the antitumor effects of sorafenib wasconfirmed in a tumor xenograft model. The present results indicatethat DN200434 may be a novel therapeutic strategy tore-sensitize HCC cells to sorafenib.
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