DN200434, an orally available inverse agonist of estrogen-related receptor gamma, induces ferroptosis in sorafenib-resistant hepatocellular carcinoma
- Authors
- Kim, Dong-Ho; Kim, Mi-Jin; Kim, Na-Young; Lee, Seunghyeong; Byun, Jun-Kyu; Yun, Jae Won; Lee, Jaebon; Jin, Jonghwa; Kim, Jina; Chin, Jungwook; Cho, Sung Jin; Lee, In-Kyu; Choi, Yeon-Kyung; Park, Keun-Gyu
- Issue Date
- 2022-11
- Publisher
- 생화학분자생물학회
- Citation
- BMB Reports, v.55, no.11, pp.547 - 552
- Abstract
- Sorafenib, originally identified as an inhibitor of multiple onco-genic 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 recep-tor estrogen-related receptor gamma (ERR gamma) 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 gamma with DN200434, an orally available inverse agonist, can over-come resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenib-induced ferroptosis and showed significantly higher ERR gamma levels than sorafenib-sensitive HCC cells. DN200434 induced lipid peroxidation and ferroptosis in sorafenib-resistant HCC cells. Me-chanistically, DN200434 increased mitochondrial ROS genera-tion by reducing glutathione/glutathione disulfide levels, which sub-sequently 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 in-dicate that DN200434 may be a novel therapeutic strategy to re-sensitize HCC cells to sorafenib. [BMB Reports 2022; 55(11): 547-552]
- Keywords
- DN200434; ERR?; Ferroptosis; Hepatocellular carcinoma; Sorafenib
- ISSN
- 1976-6696
- URI
- https://pubs.kist.re.kr/handle/201004/114280
- DOI
- 10.5483/BMBRep.2022.55.11.089
- Appears in Collections:
- KIST Article > 2022
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