Tumor mitochondrial oxidative phosphorylation stimulated by the nuclear receptor RORγ represents an effective therapeutic opportunity in osteosarcoma

• Published in: Cell reports. Medicine Vol. 5; no. 5; p. 101519
• Main Authors: Zheng, Jianwei, Wang, Qianqian, Chen, Jianghe, Cai, Guodi, Zhang, Zhenhua, Zou, Hongye, Zou, June X., Liu, Qianqian, Ji, Shufeng, Shao, Guoli, Li, Hong, Li, Sheng, Chen, Hong-Wu, Lu, LinLin, Yuan, Yanqiu, Liu, Peiqing, Wang, Junjian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-05-2024; Elsevier
• Subjects: Animals; Apoptosis - drug effects; Bone Neoplasms - drug therapy; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation; Ferroptosis - drug effects; Ferroptosis - genetics; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Nude; Mitochondria - metabolism; Mitochondria - pathology; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Osteosarcoma - genetics; Osteosarcoma - metabolism; Osteosarcoma - pathology; Oxidative Phosphorylation - drug effects; Reactive Oxygen Species - metabolism; RNA-Binding Proteins
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101519

Osteosarcoma (OS) is the most common malignant bone tumor with a poor prognosis. Here, we show that the nuclear receptor RORγ may serve as a potential therapeutic target in OS. OS exhibits a hyperactivated oxidative phosphorylation (OXPHOS) program, which fuels the carbon source to promote tumor progression. We found that RORγ is overexpressed in OS tumors and is linked to hyperactivated OXPHOS. RORγ induces the expression of PGC-1β and physically interacts with it to activate the OXPHOS program by upregulating the expression of respiratory chain component genes. Inhibition of RORγ strongly inhibits OXPHOS activation, downregulates mitochondrial functions, and increases ROS production, which results in OS cell apoptosis and ferroptosis. RORγ inverse agonists strongly suppressed OS tumor growth and progression and sensitized OS tumors to chemotherapy. Taken together, our results indicate that RORγ is a critical regulator of the OXPHOS program in OS and provides an effective therapeutic strategy for this deadly disease.
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•RORγ is overexpressed in OS tumor cells and is linked to hyperactivated OXPHOS•RORγ physically interacts with PGC-1β to control OXPHOS and mitochondrial function•RORγ inhibition induces apoptosis and ferroptosis by inhibiting OXPHOS activation•RORγ inverse agonists suppress OS tumor growth and sensitize it to chemotherapy
Osteosarcoma (OS) exhibits hyperactivated OXPHOS program, which fuels the carbon source to promote tumor progression. Zheng et al. uncover that RORγ formed a positive regulatory loop with PGC-1β to directly activate ETC components to enhance OXPHOS in OS. Targeting RORγ blocks OS tumor progression via suppressing OXPHOS program.