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DN200434, an Orally Available Inverse Agonist of Estrogen-Related Receptor ャ, Induces Ferroptosis in Sorafenib-Resistant Hepatocellular Carcinoma
Dong-Ho Kim1,# (PhD student), Mi-Jin Kim2,3,# (PhD), Na-Young Kim3,# (PhD), Seunghyeong Lee3 (PhD), Jun-Kyu Byun2,3 (PhD), Jae Won Yun4 (PhD), Jaebon Lee5 (MD), Jonghwa Jin3 (MD), Jungwook Chin6 (PhD), Sung Jin Cho7 (PhD), In-Kyu Lee1,2,3 (Professor), Yeon-Kyung Choi2,3,* (Assistant professor), Keun-Gyu Park1,2,3 (Professor)
1Department of Biomedical Science and 2Research Institute of Aging and Metabolism and 3Department of Internal Medicine, Kyungpook National University,
4Veterans Medical Research Institute, Veterans Health Service Medical Center,
5School of Medicine, Sungkyunkwan University,
6New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation
Abstract
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 ャ (ERRャ) 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ャ 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ャ 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.
Abstract, Accepted Manuscript(in press) [Submitted on May 23, 2022, Accepted on August 1, 2022]
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