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Targeting the NR3C1-ACSL4 Axis Triggers Ferroptosis to Overcome Radioresistance in Prostate Cancer
Jing Yang1,2, Puyuan Chen1, Yawen Zheng1,3
1Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, P. R. China.
Abstract:
Radioresistance in prostate cancer demands innovative sensitization strategies. We identified the glucocorticoid receptor nuclear receptor subfamily 3 group C member 1 (NR3C1) as a key negative regulator of radiosensitivity linked to poor prognosis. NR3C1 transcriptionally upregulates the lipid-metabolizing enzyme, acyl-CoA synthetase long-chain family member 4 (ACSL4), thereby enhancing cell proliferation, migration, and radioresistance. High ACSL4 expression sensitizes cells to ferroptosis inducers that amplify lipid peroxidation and restore radiosensitivity. Using the clinically applicable ferroptosis inducer, dihydroartemisinin (DHA), we found that DHA synergizes with ACSL4 to trigger ferroptosis, sensitizing radioresistant cells and xenografts to radiation. This effect was characterized by elevated lipid peroxidation and was reversed by the ferroptosis inhibitor deferoxamine. Collectively, our study revealed that the NR3C1-ACSL4 axis regulates lipid peroxidation and promotes radioresistance. Targeting this axis with DHA and using ACSL4 as a biomarker represents a promising preclinical strategy to overcome radioresistance in prostate cancer, pending further clinical validation.
Insights
Prostate cancer radioresistance is linked to the NR3C1-ACSL4 pathway. Targeting this axis with dihydroartemisinin (DHA) sensitizes resistant cells to radiation by inducing ferroptosis, offering a potential new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Prostate cancer radioresistance poses a significant clinical challenge.
- The glucocorticoid receptor (NR3C1) is identified as a key regulator impacting patient prognosis.
- NR3C1's role in promoting radioresistance requires further elucidation.
Purpose of the Study:
- To investigate the NR3C1-ACSL4 axis in prostate cancer radioresistance.
- To explore the potential of targeting this axis with ferroptosis inducers for radiosensitization.
Main Methods:
- Identified NR3C1 as a regulator of radiosensitivity.
- Investigated the role of acyl-CoA synthetase long-chain family member 4 (ACSL4) in mediating NR3C1 effects.
- Utilized the ferroptosis inducer dihydroartemisinin (DHA) in radioresistant prostate cancer models.
- Assessed lipid peroxidation and ferroptosis induction.
- Evaluated radiosensitization in cell lines and xenografts.
Main Results:
- NR3C1 transcriptionally upregulates ACSL4, promoting proliferation, migration, and radioresistance.
- High ACSL4 expression sensitizes cells to ferroptosis and restores radiosensitivity.
- DHA synergizes with ACSL4 to induce ferroptosis and sensitize radioresistant prostate cancer cells and xenografts to radiation.
- The observed effects were linked to increased lipid peroxidation and reversed by deferoxamine.
Conclusions:
- The NR3C1-ACSL4 axis is a critical regulator of lipid peroxidation and prostate cancer radioresistance.
- Targeting the NR3C1-ACSL4 axis with DHA presents a promising preclinical strategy to overcome radioresistance.
- ACSL4 may serve as a predictive biomarker for this therapeutic approach.
