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Inhibition of PREX1 Reverses Enzalutamide Resistance in Castration-Resistant Prostate Cancer
Chung Un Lee1, Seon-Yong Yeom2, Wan Song2
1Department of Urology, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong, Korea.
Purpose:
Castration-resistant prostate cancer (CRPC) often progresses despite initial responses to enzalutamide owing to the development of resistance. Our study explored the mechanisms underlying resistance in enzalutamide-resistant prostate cancer cell lines, along with the role of phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger 1 (PREX1) in CRPC resistance.
Materials And Methods:
The sequencing of total RNA was performed to analyze the microarray gene expression profiles. In our colony formation assay, 1,000 cells per well were seeded into six-well plates to evaluate clonogenic survival. Phosphoprotein profiling was conducted to assess specific signaling pathways and estimate cell proliferation rates. Protein expression was analyzed by western blotting, and Rac GTPase activity was measured to evaluate the cellular responses to enzalutamide. Cell invasion was examined using Transwell migration assays. An in vivo model involving the subcutaneous implantation of tumor cells into mice was used to study tumorigenic potential under resistant conditions.
Results:
RNA sequencing revealed activation of the cancer migration pathway in enzalutamide-resistant prostate cancer cells with significant upregulation of PREX1. PREX1 knockdown reduced the proliferation and colony formation rates of resistant cell lines. Mechanistically, PREX1 suppression inhibited both epidermal growth factor receptor and its downstream signaling pathways, including signal transducers and activators of transcription 5, thereby reducing cell migration and epithelial-mesenchymal transition, independent of Rac activation. In vivo, tumors derived from PREX1-knockdown cells exhibited significantly lower weights than those derived from control cells.
Conclusions:
This study provides compelling evidence on the pivotal role of PREX1 in mediating enzalutamide resistance in CRPC. Our findings suggest that PREX1 is a promising therapeutic target that may modulate treatment efficacy and drug resistance in CRPC.
Insights
Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger 1 (PREX1) drives enzalutamide resistance in castration-resistant prostate cancer (CRPC). Targeting PREX1 may improve treatment efficacy for CRPC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Castration-resistant prostate cancer (CRPC) frequently develops resistance to enzalutamide therapy.
- Understanding the molecular mechanisms of enzalutamide resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the mechanisms of enzalutamide resistance in CRPC.
- To explore the role of phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger 1 (PREX1) in mediating CRPC resistance.
Main Methods:
- RNA sequencing and gene expression profiling.
- Cell proliferation, colony formation, and invasion assays.
- Western blotting, phosphoprotein profiling, and in vivo tumor xenograft models.
Main Results:
- Enzalutamide-resistant CRPC cells showed upregulation of PREX1 and activation of cancer migration pathways.
- PREX1 knockdown reduced cell proliferation, colony formation, and migration by inhibiting EGFR signaling.
- Tumor growth was significantly reduced in vivo following PREX1 knockdown.
Conclusions:
- PREX1 plays a critical role in mediating enzalutamide resistance in CRPC.
- PREX1 represents a potential therapeutic target to overcome drug resistance and enhance treatment efficacy in CRPC.
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