Glutamine transporters regulate prostate cancer radiosensitivity through NUPR1-mediated stress response

Prostate cancer (PCa) presents a significant clinical challenge due to its resistance to conventional therapies such as radiotherapy (RT), which is exacerbated in advanced stages by metabolic and stress response adaptations. Our study investigates the roles of amino acid transporters SLC1A5, SLC7A5, and SLC38A1, in regulating NUPR1-mediated stress response, PCa cell survival, metabolic reprogramming, and response to RT. Depletion of these transporters disrupted glutamine (Gln) uptake, leading to reduced cell viability, altered ROS levels, and enhanced radiosensitivity in DU145 and LNCaP cell lines. Functional assays revealed that targeting these transporters decreases stem cell-like properties, impairs cell cycle progression, and heightens DNA damage under RT. Besides, CB839, a glutaminase inhibitor, combined with RT, demonstrated a synergistic effect in vivo, significantly delaying tumor growth compared to other treatment groups. Our findings indicate that these transporters mediate PCa cells’ adaptation to nutrient stress, while NUPR1 promotes cellular survival under metabolic and genotoxic stress. The results highlight the therapeutic potential of targeting Gln metabolism and stress response pathways to improve treatment efficacy. Our findings indicate that targeting SLC1A5, SLC7A5, SLC38A1, and NUPR1 radiosensitizes PCa by disrupting metabolic adaptations and stress responses. These findings provide a potential therapeutic strategy to enhance the efficacy of RT and improve treatment outcomes for PCa patients.