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Cell Reports Medicine

Cell Reports Medicine

IF: 11.7
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Tumor mitochondrial oxidative phosphorylation stimulated by the nuclear receptor RORγ represents an effective therapeutic opportunity in osteosarcoma

Published:30 April 2024 DOI: 10.1016/j.xcrm.2024.101519
Jianwei Zheng, Qianqian Wang, Jianghe Chen, Guodi Cai, Zhenhua Zhang, Hongye Zou, June X. Zou, Qianqian Liu, Shufeng Ji, Guoli Shao, Hong Li, Sheng Li, Hong-Wu Chen, LinLin Lu, Yanqiu Yuan, Peiqing Liu, Junjian Wang

Abstract

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.

Substances (20)

Materials
Procduct Name CAS Molecular Formula Supplier Price
2-[1-[4-[2-(4-Chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4(3H)-Quinazolinone 571203-78-6 C30H31ClN4O4 285 suppliers $16.00-$2691.10
2-[1-[4-[2-(4-Chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4(3H)-Quinazolinone 571203-78-6 C30H31ClN4O4 285 suppliers $16.00-$2691.10
2-[1-[4-[2-(4-Chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4(3H)-Quinazolinone 571203-78-6 C30H31ClN4O4 285 suppliers $16.00-$2691.10
2-[1-[4-[2-(4-Chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4(3H)-Quinazolinone 571203-78-6 C30H31ClN4O4 285 suppliers $16.00-$2691.10
Ferrostatin-1 (Fer-1) 347174-05-4 C15H22N2O2 249 suppliers $10.00-$2822.00
Ferrostatin-1 (Fer-1) 347174-05-4 C15H22N2O2 249 suppliers $10.00-$2822.00
Ferrostatin-1 (Fer-1) 347174-05-4 C15H22N2O2 249 suppliers $10.00-$2822.00
Ferrostatin-1 (Fer-1) 347174-05-4 C15H22N2O2 249 suppliers $10.00-$2822.00
5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole 1570496-34-2 C25H25F3N6O4S 112 suppliers $27.00-$4722.00
5-(5-methyl-1-(3-(4-(methylsulfonyl)piperidin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole 1570496-34-2 C25H25F3N6O4S 112 suppliers $27.00-$4722.00

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