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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Loss of GPR133 Promotes Enzalutamide Resistance in Prostate Cancer by Upregulating HSD3B1 and Intratumoral Androgen
Lai Wei1, Ziwei Wang1, Dajun Gao1
1Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Background:
The progression of prostate cancer (PCa) to a castration-resistant state (CRPC) remains a major clinical challenge. Resistance to second-generation androgen receptor (AR) antagonists like enzalutamide often involves the reactivation of AR signaling, frequently through intratumoral androgen synthesis. The molecular drivers that regulate this adaptive resistance mechanism are not fully understood. GPR133 (also known as ADGRD1) is an adhesion G protein-coupled receptor with emerging roles in various cancers, but its function in prostate cancer is unknown. While androgen signaling is classically mediated by the nuclear AR, GPR133 has recently been identified as a novel membrane androgen receptor, though its functional relationship with the AR pathway in prostate cancer is unknown.
Methods:
We analyzed GPR133 expression in patient-derived PCa tissues and its correlation with clinical outcomes using publicly available datasets and our patients' samples. We employed gain- and loss-of-function approaches in vitro to test whether GPR133 specifically mediates resistance to enzalutamide. RNA sequencing was used to identify downstream pathways regulated by GPR133. The role of the downstream effector HSD3B1 was assessed using siRNA-mediated silencing. The therapeutic implications of GPR133 expression were validated in vivo using xenograft mouse models.
Results:
GPR133 expression is significantly downregulated in prostate cancer tissue compared to benign tissue and is further decreased in CRPC. Low GPR133 expression correlates with poorer disease-free survival. Silencing GPR133 conferred robust resistance to enzalutamide in vitro and in vivo. Conversely, overexpression of GPR133 could further sensitize cancer cells to enzalutamide. Mechanistically, loss of GPR133 transcriptionally upregulated key enzymes in the steroid hormone biosynthesis pathway, most notably HSD3B1. This upregulation led to elevated intracellular testosterone levels and sustained androgen receptor (AR) signaling, characterized by the persistent expression of AR target genes despite enzalutamide treatment. Silencing HSD3B1 reversed the enzalutamide resistance induced by GPR133 knockdown.
Conclusions:
Our findings identify GPR133 as a novel tumor suppressor in prostate cancer. Loss of GPR133 expression is a key event in the progression to CRPC that promotes therapeutic resistance by activating the intratumoral androgen synthesis pathway. GPR133 may serve as a valuable prognostic biomarker and a potential therapeutic target for advanced prostate cancer.
Insights
Loss of GPR133 promotes prostate cancer (PCa) resistance to enzalutamide by increasing intratumoral androgen synthesis. Restoring GPR133 may overcome treatment resistance in advanced PCa.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Prostate cancer (PCa) progression to castration-resistant PCa (CRPC) is a clinical challenge.
- Resistance to enzalutamide often involves androgen receptor (AR) signaling reactivation via intratumoral androgen synthesis.
- GPR133 (ADGRD1), a G protein-coupled receptor, has emerging roles in cancer, but its function in PCa and relationship with AR signaling are unknown.
Purpose of the Study:
- To investigate the role of GPR133 in PCa progression and resistance to enzalutamide.
- To elucidate the molecular mechanisms by which GPR133 influences AR signaling and therapeutic response.
- To evaluate GPR133 as a potential biomarker and therapeutic target in PCa.
Main Methods:
- Analysis of GPR133 expression in PCa tissues and correlation with clinical outcomes.
- In vitro gain- and loss-of-function studies to assess GPR133's role in enzalutamide resistance.
- RNA sequencing to identify GPR133-regulated pathways, including HSD3B1.
- In vivo validation using xenograft mouse models.
Main Results:
- GPR133 expression is downregulated in PCa, particularly in CRPC, correlating with poorer survival.
- GPR133 loss confers enzalutamide resistance in vitro and in vivo; GPR133 overexpression sensitizes cells to enzalutamide.
- GPR133 loss upregulates HSD3B1, increasing intracellular testosterone and sustaining AR signaling.
- HSD3B1 silencing reverses enzalutamide resistance caused by GPR133 knockdown.
Conclusions:
- GPR133 acts as a tumor suppressor in PCa.
- Loss of GPR133 promotes CRPC progression and therapeutic resistance by activating intratumoral androgen synthesis.
- GPR133 is a potential prognostic biomarker and therapeutic target for advanced PCa.
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