The world journal of men's health · 2025
Inhibition of PREX1 Reverses Enzalutamide Resistance in Castration-Resistant Prostate Cancer.
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Lee Chung Un, Yeom Seon-Yong, Song Wan, Kang Minyong, Sung Hyun Hwan, Jeon Hwang Gyun, Jeong Byong Chang, Jeon Seong Soo, Seo Seong Il
Аннотация
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.
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.