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Our study investigated the roles of glutamine (Gln) transporters\n                      <jats:italic>SLC1A5<\/jats:italic>\n                      ,\n                      <jats:italic>SLC7A5<\/jats:italic>\n                      , and\n                      <jats:italic>SLC38A1<\/jats:italic>\n                      in regulating\n                      <jats:italic>NUPR1<\/jats:italic>\n                      -mediated stress response, PCa cell survival, metabolic reprogramming, and response to RT.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The radiosensitizing potential of GLS inhibition with CB-839 was analyzed in prostate cancer xenograft models. The level of gene expression was analyzed by RNA sequencing and RT-qPCR in the established cell lines or patient-derived tumor and adjacent non-cancerous tissues. Phosphoproteomic analysis was employed to identify the underlying signaling pathways. The publicly available PCa patient datasets, and a dataset for the patients treated with RT were analyzed by SUMO software. The key parameters of mitochondrial functions were measured by Seahorse analysis. Analysis of the general oxidative stress level and mitochondrial superoxide detection were conducted using flow cytometry. \u03b3H2A.X foci analysis was used to assess the DNA double strand break. Relative cell sensitivity to RT was evaluated by radiobiological clonogenic assays. Aldefluor assay and sphere-forming analysis were used to determine cancer stem cell (CSC) phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A siRNA-mediated knockdown of Gln transporters\n                      <jats:italic>SLC1A5<\/jats:italic>\n                      ,\n                      <jats:italic>SLC7A5<\/jats:italic>\n                      , and\n                      <jats:italic>SLC38A1<\/jats:italic>\n                      resulted in significant radiosensitization of PCa cells. Consistently, the first-in-clinic glutaminase (GLS) inhibitor CB-839, combined with RT, demonstrated a synergistic effect with radiotherapy in vivo, significantly delaying tumor growth. Inhibition of Gln metabolism or knockdown of Gln transporters\n                      <jats:italic>SLC1A5<\/jats:italic>\n                      ,\n                      <jats:italic>SLC7A5<\/jats:italic>\n                      , or\n                      <jats:italic>SLC38A1<\/jats:italic>\n                      induces expression of\n                      <jats:italic>NUPR1<\/jats:italic>\n                      , a stress response transcriptional regulator, but simultaneously uncouples the NUPR1-driven metabolic stress-adaptation program. Similarly to the effect from\n                      <jats:italic>NUPR1<\/jats:italic>\n                      knockdown, depletion of these Gln transporters led to reduced cell viability, accumulation of mitochondrial ROS, and increased PCa radiosensitivity. This effect is more pronounced in PCa cells with high dependency on OXPHOS for energy production.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our work underscores the role of Gln transporters and the NUPR1-mediated stress response in PCa cell survival, oxidative stress, mitochondrial functions, and radioresistance. Our findings provide a potential therapeutic in vivo strategy to enhance the efficacy of RT and suggest a potential synergism between the depletion of Gln transporters or NUPR1 and OXPHOS inhibition.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12964-025-02344-3","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T15:11:34Z","timestamp":1753369894000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Disruption of glutamine transport uncouples the NUPR1 stress-adaptation program and induces prostate cancer radiosensitivity"],"prefix":"10.1186","volume":"23","author":[{"given":"U\u011fur","family":"Kahya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasyl","family":"Lukiyanchuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ielizaveta","family":"Gorodetska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias M.","family":"Weigel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ay\u015fe Sedef","family":"K\u00f6seer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berke","family":"Alkan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragana","family":"Savic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annett","family":"Linge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"L\u00f6ck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirko","family":"Peitzsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ira-Ida","family":"Skvortsova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mechthild","family":"Krause","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Dubrovska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,24]]},"reference":[{"issue":"3","key":"2344_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. 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