Loss of GPR133: A Key Driver of Enzalutamide Resistance in Prostate Cancer

The progression of prostate cancer to a castration-resistant state (CRPC) remains a significant clinical challenge for urologists globally. Resistance to second-generation androgen receptor (AR) antagonists often involves the reactivation of signaling pathways. Specifically, enzalutamide resistance prostate cancer frequently stems from increased intratumoral androgen synthesis. Researchers recently identified GPR133, an adhesion G protein-coupled receptor, as a novel membrane androgen receptor. Its role in prostate malignancy, however, was previously unknown.

Mechanisms of Enzalutamide Resistance Prostate Cancer

A recent study published in Prostate reveals that GPR133 acts as a potent tumor suppressor. Analysis of patient-derived tissues shows that GPR133 expression is significantly lower in cancerous tissue compared to benign samples. Moreover, expression levels drop further as the disease progresses to CRPC. Low GPR133 levels correlate strongly with poorer disease-free survival. Consequently, the loss of this receptor serves as a critical event in therapeutic failure.

Mechanistically, the loss of GPR133 transcriptionally upregulates key enzymes in the steroid hormone biosynthesis pathway. The most notable enzyme is HSD3B1. This upregulation leads to elevated intracellular testosterone levels. Furthermore, these increased androgen levels sustain AR signaling despite enzalutamide treatment. Therefore, the tumor effectively bypasses the drug's inhibitory effects by producing its own fuel.

Therapeutic Implications and Future Outlook

The research also demonstrates that silencing HSD3B1 can reverse the resistance induced by GPR133 knockdown. Additionally, overexpressing GPR133 can sensitize cancer cells to enzalutamide. These findings suggest that GPR133 could serve as both a valuable prognostic biomarker and a potential therapeutic target. In contrast to current treatments, targeting this pathway might prevent the metabolic adaptations that lead to enzalutamide resistance prostate cancer.

Frequently Asked Questions

What is GPR133's role in prostate cancer?

GPR133 functions as a tumor suppressor and a membrane androgen receptor. Its loss promotes the progression to castration-resistant prostate cancer and drives resistance to therapies like enzalutamide.

How does HSD3B1 contribute to drug resistance?

HSD3B1 is a key enzyme in the steroid biosynthesis pathway. When upregulated due to GPR133 loss, it increases intratumoral testosterone production, allowing cancer cells to maintain growth signaling even during treatment.

Can enzalutamide resistance be reversed?

Experimental models suggest that silencing the HSD3B1 enzyme or restoring GPR133 expression can resensitize prostate cancer cells to enzalutamide treatment.

Disclaimer: This content is for informational and educational purposes only and does not constitute medical advice. Always seek the advice of a qualified healthcare provider with any questions regarding a medical condition. Refer to the latest local and national guidelines for clinical practice.

References

Wei L et al. Loss of GPR133 Promotes Enzalutamide Resistance in Prostate Cancer by Upregulating HSD3B1 and Intratumoral Androgen Synthesis. Prostate. 2026 Feb 10. doi: 10.1002/pros.70138. PMID: 41664980.

Hearn JWD et al. HSD3B1 and resistance to castration-resistant prostate cancer therapies. J Clin Invest. 2023;133(22):e165718.

Yuan X, Balk SP. Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy. Endocr Relat Cancer. 2011;18(3):R45-59.