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Updated: Jun 27, 2025
Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells In Vitro
Published on: March 18, 2014
Tumor mitochondrial oxidative phosphorylation stimulated by the nuclear receptor RORγ represents an effective
Jianwei Zheng1, Qianqian Wang1, Jianghe Chen1
1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China.
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.
Insights
Nuclear receptor RORγ is overexpressed in osteosarcoma (OS), driving oxidative phosphorylation (OXPHOS). Inhibiting RORγ suppresses tumor growth and sensitizes OS to chemotherapy, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- Osteosarcoma (OS) is a prevalent and aggressive bone cancer with limited treatment options.
- A hyperactivated oxidative phosphorylation (OXPHOS) pathway is crucial for OS tumor progression.
Purpose of the Study:
- To investigate the role of the nuclear receptor RORγ in osteosarcoma.
- To evaluate RORγ as a potential therapeutic target for OS.
Main Methods:
- Analysis of RORγ expression in OS tumors.
- Investigating the interaction between RORγ and PGC-1β.
- Assessing the impact of RORγ inhibition on OXPHOS, mitochondrial function, and cell death.
- Evaluating RORγ inverse agonists in preclinical OS models.
Main Results:
- RORγ is overexpressed in OS and linked to hyperactivated OXPHOS.
- RORγ upregulates OXPHOS by inducing PGC-1β and activating respiratory chain genes.
- RORγ inhibition impairs mitochondrial function, increases ROS, and induces apoptosis and ferroptosis.
- RORγ inverse agonists significantly inhibit OS tumor growth and enhance chemotherapy efficacy.
Conclusions:
- RORγ is a key regulator of the OXPHOS program in osteosarcoma.
- Targeting RORγ represents a promising therapeutic strategy for osteosarcoma.
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