Androgen Receptor Variants Confer Castration Resistance in Prostate Cancer by Counteracting Antiandrogen-Induced Ferroptosis

Androgen receptor (AR) inhibition by androgen deprivation and/or antiandrogen administration is the mainstay therapy for advanced prostate cancer. However, most prostate cancers ultimately become resistant to these therapies, indicating the importance of identifying mechanisms driving resistance to improve patient outcomes. Here we demonstrated that acute treatment with the antiandrogen enzalutamide (ENZ) decreased glutathione (GSH) production, increased lipid peroxidation, and induced ferroptosis in prostate cancer cells. Consistently, meta-analysis of transcriptomic data linked the androgen-AR axis to metabolism-related biological processes, including lipid metabolism. The cystine transporter gene SLC7A11 was a key AR target, and full-length AR (AR-FL) transactivated SLC7A11 transcription by directly occupying the SLC7A11 promoter and putative enhancer regions. AR variants (AR-V) preferentially bound the SLC7A11 enhancer and upregulated SLC7A11 expression, thereby conferring resistance to ferroptosis induced by ENZ treatment. However, this effect was abolished following downregulation of AR-Vs using the dual CBP/p300 and BET inhibitor NEO2734. These findings reveal ferroptosis induction as an anticancer mechanism of antiandrogens and SLC7A11 as a direct target gene of AR-FL and AR-Vs. AR-V-mediated SLC7A11 expression represents a mechanism coupling ferroptosis resistance to prostate cancer progression.

 

Comments:

The passage you provided discusses the mechanisms of resistance that prostate cancer cells develop against antiandrogen therapy, specifically focusing on the drug enzalutamide (ENZ). Here's a breakdown of the key points mentioned in the passage:

1. **Background:** Androgen receptor (AR) inhibition through androgen deprivation therapy and antiandrogen administration is a standard treatment for advanced prostate cancer.

2. **Resistance to Therapy:** Despite initial effectiveness, many prostate cancers eventually become resistant to these therapies. Understanding the mechanisms behind this resistance is crucial for improving patient outcomes.

3. **ENZ Treatment Effects:** Acute treatment with the antiandrogen drug enzalutamide (ENZ) leads to several changes in prostate cancer cells:
   - Decreased production of glutathione (GSH).
   - Increased lipid peroxidation.
   - Induction of ferroptosis, a form of regulated cell death involving iron-dependent lipid peroxidation.

4. **Transcriptomic Analysis:** Analysis of gene expression data (transcriptomic data) revealed a connection between the androgen-AR axis and processes related to metabolism, particularly lipid metabolism.

5. **Role of SLC7A11:** The gene SLC7A11, which codes for the cystine transporter, was identified as a key target of AR. Both full-length AR (AR-FL) and AR variants (AR-Vs) influenced the expression of SLC7A11.

6. **AR Regulation:** AR-FL directly activated the transcription of SLC7A11 by binding to specific regions in its promoter and enhancer. AR-Vs, which are variant forms of the androgen receptor, preferentially bound to the enhancer of SLC7A11, increasing its expression.

7. **Ferroptosis Resistance:** Elevated SLC7A11 expression, mediated by AR-Vs, conferred resistance to ferroptosis induced by ENZ treatment. Ferroptosis resistance is implicated in the progression of prostate cancer.

8. **Intervention:** The resistance conferred by AR-Vs was overcome by downregulating their expression using a dual inhibitor called NEO2734, which targets CBP/p300 and BET proteins. This intervention abolished the ferroptosis resistance associated with AR-Vs.

In summary, the passage describes the molecular mechanisms underlying resistance to antiandrogen therapy in prostate cancer. It highlights the role of ferroptosis, lipid metabolism, and the regulation of SLC7A11 by both AR-FL and AR-Vs. The study suggests that targeting these mechanisms could be a potential avenue for developing more effective treatments for advanced prostate cancer.

Related Products

Cat.No.	Product Name	Information
S9648	NEO2734	NEO2734 (EP31670) is a novel, orally active and selective dual inhibitor of p300/CBP and BET bromodomain with IC50 of both <30 nM.

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Histone Acetyltransferase Epigenetic Reader Domain