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Peer-reviewedCC BYCell death discovery

Glutamine synthesis pathway promotes the survival and recurrence of dormant tumor cells in prostate cancer.

  • Bing Zhao1
  • Qingwei Meng2,3,4
  • Jun Zhou2,3,4
  • Kun He2,3,4
  • Hekang Ding2,3,4
  • Jing Wang5
  • Hailiang Hu6,7
  • Lingfan Xu8,9,10
10 affiliations
  1. 1Department of Geriatrics, Anhui Key Laboratory of Geriatric Immunology and Nutritional Therapy, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
  2. 2Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230001, China.
  3. 3Institute of Urology, Anhui Medical University, Hefei, 230001, China.
  4. 4Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, 230001, China.
  5. 5Department of Urologic Oncology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230031, China. [email protected].
  6. 6Department of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China. [email protected].
  7. 7Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, 518055, China. [email protected].
  8. 8Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230001, China. [email protected].
  9. 9Institute of Urology, Anhui Medical University, Hefei, 230001, China. [email protected].
  10. 10Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, 230001, China. [email protected].
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Abstract

Cancer cell dormancy presents a major obstacle to curative therapy, particularly in metastatic prostate cancer. Although the initial efficacy of hormonal therapy is satisfying, tumors will inevitably develop resistance. Dormant tumor cells may act as the initial source for the tumor recurrence, but the underlying mechanism remains largely unknown. Here we report that the glutamine synthesis pathway is required for cellular dormancy under androgen-deprived conditions. The key enzyme, glutamine synthetase (encoded by glutamate-ammonia ligase, GLUL), is upregulated during hormonal therapy, which leads to overabundant glutamine as a nutrient and an energy storage for tumor recurrence. The negative modulation of androgen receptor (AR) on GLUL enables activation of glutamine anabolism when AR is inhibited. Pharmacologically inhibiting GS's activity along with hormonal therapy results in cell apoptosis instead of dormancy, which significantly delays the progression of tumors into advanced PCa. In summary, we provide a novel perspective of how hormonal therapy eventually fails and highlight a combination treatment strategy to overcome therapeutic resistance of current hormonal therapy.

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Cite

BibTeXRIS
BibTeX
@article{zhao2026glutamine,
  title = {{Glutamine synthesis pathway promotes the survival and recurrence of dormant tumor cells in prostate cancer.}},
  author = {Bing Zhao and Qingwei Meng and Jun Zhou and Kun He and Hekang Ding and Jing Wang and Hailiang Hu and Lingfan Xu},
  journal = {Cell death discovery},
  year = {2026},
  month = aug,
  doi = {10.1038/s41420-026-03282-w},
  url = {https://europepmc.org/article/MED/42901920},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Glutamine synthesis pathway promotes the survival and recurrence of dormant tumor cells in prostate cancer.
AU  - Bing Zhao
AU  - Qingwei Meng
AU  - Jun Zhou
AU  - Kun He
AU  - Hekang Ding
AU  - Jing Wang
AU  - Hailiang Hu
AU  - Lingfan Xu
PY  - 2026
DA  - 2026/08/01
JO  - Cell death discovery
DO  - 10.1038/s41420-026-03282-w
UR  - https://europepmc.org/article/MED/42901920
AB  - Cancer cell dormancy presents a major obstacle to curative therapy, particularly in metastatic prostate cancer. Although the initial efficacy of hormonal therapy is satisfying, tumors will inevitably develop resistance. Dormant tumor cells may act as the initial source for the tumor recurrence, but the underlying mechanism remains largely unknown. Here we report that the glutamine synthesis pathway is required for cellular dormancy under androgen-deprived conditions. The key enzyme, glutamine synthetase (encoded by glutamate-ammonia ligase, GLUL), is upregulated during hormonal therapy, which leads to overabundant glutamine as a nutrient and an energy storage for tumor recurrence. The negative modulation of androgen receptor (AR) on GLUL enables activation of glutamine anabolism when AR is inhibited. Pharmacologically inhibiting GS's activity along with hormonal therapy results in cell apoptosis instead of dormancy, which significantly delays the progression of tumors into advanced PCa. In summary, we provide a novel perspective of how hormonal therapy eventually fails and highlight a combination treatment strategy to overcome therapeutic resistance of current hormonal therapy.
SN  - 2058-7716
ER  -