TXNIP upregulation controls metabolism and cell cycle during androgen deprivation therapy in prostate cancer

  • Cell Death Dis. 2025 Nov 10;16(1):817. doi: 10.1038/s41419-025-08128-4.
Sergio Alcon-Rodriguez  1  2  3 ,  Juan C Mayo  1  2  3 ,  Pedro Gonzalez-Menendez  1  2  3 ,  Iván Fernandez-Vega  3  4  5 ,  David Hevia  1  2  3 ,  Sheila Fernandez-Vega  1  2  3 ,  Alba Moran-Alvarez  1  2  3 ,  Daniela Pineda-Cevallos  3  6 ,  Miguel Alvarez-Mugica  7 ,  Pablo Rodriguez-Gonzalez  3  6 ,  Belen Garcia-Soler  1  2  3 ,  Jorge Zamora  8  9  10 ,  Jose M C Tubio  8  9  10 ,  Rosa M Sainz  11  12  13 ,  Isabel Quiros-Gonzalez  14  15  16
Affiliations
  • 1. Department of Morphology and Cell Biology, School of Medicine, University of Oviedo, Oviedo, Spain.
  • 2. Oncology Institute of Principado de Asturias (IUOPA), Oviedo, Spain.
  • 3. Health Research Institute of Principado de Asturias (ISPA), Oviedo, Spain.
  • 4. Department of Pathology, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.
  • 5. Biobank of the Principality of Asturias (BioPA), Oviedo, Spain.
  • 6. Department of Physical and Analytical Chemistry, School of Chemistry, University of Oviedo, Oviedo, Spain.
  • 7. Department of Urology, Hospital Valle del Nalón, Langreo, Spain.
  • 8. Mobile Genomes, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
  • 9. Instituto de Investigaciones Sanitarias de Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
  • 10. Department of Zoology, Genetics and Physical Anthropology, Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
  • 11. Department of Morphology and Cell Biology, School of Medicine, University of Oviedo, Oviedo, Spain. [email protected].
  • 12. Oncology Institute of Principado de Asturias (IUOPA), Oviedo, Spain. [email protected].
  • 13. Health Research Institute of Principado de Asturias (ISPA), Oviedo, Spain. [email protected].
  • 14. Department of Morphology and Cell Biology, School of Medicine, University of Oviedo, Oviedo, Spain. [email protected].
  • 15. Oncology Institute of Principado de Asturias (IUOPA), Oviedo, Spain. [email protected].
  • 16. Health Research Institute of Principado de Asturias (ISPA), Oviedo, Spain. [email protected].
PMID: 41213907 DOI: 10.1038/s41419-025-08128-4
Abstract

Thioredoxin-Interacting Protein (TXNIP) is an Arrestin at the crossroad of redox and glycolytic metabolisms. Prostate Cancer (PCa) exhibits a unique metabolic profile due to the glycolytic nature of healthy prostate tissue. We hypothesize that TXNIP plays a pivotal role in the progression of PCa to castration-resistant prostate Cancer (CRPC), an incurable stage of the disease characterized by profound metabolic reprogramming and independence from androgens. Only a subset of patients progresses to CRPC, and current stratification tools lack robust biomarkers. TXNIP expression is directly suppressed by androgens and diminishes during tumor initiation and progression, as demonstrated in both human samples and a prostate adenocarcinoma mouse model (TRAMP). TXNIP regulates glucose metabolism by sequestering the glucose transporter GLUT1 away from the membrane, shifting metabolism from glycolysis to glutaminolysis. Nuclear-localized TXNIP induces cell cycle arrest through the upregulation of p27kip1 which is downregulated together with TXNIP in CRPC. The response to androgen deprivation therapy (ADT) strongly depends on TXNIP expression. In the murine model, TXNIP levels were significantly higher in ADT responders compared to non-responders. Furthermore, TRAMP-Txnip-/- prostate tumors exhibited a poorer response to ADT, with increased Ki67 and enhanced viability. In clinical samples, all patients on relapse showed low levels of TXNIP and progressed to CRPC. Our findings identify TXNIP as a critical regulator of cell cycle and glucose metabolism in PCa and emphasize for the first time its essential role in mediating therapeutic responses to ADT.

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