Targeting the glutamine metabolism to suppress cell proliferation in mesenchymal docetaxel-resistant prostate cancer.

Autor: Beier AK; Department of Urology, Technische Universität Dresden, Dresden, Germany., Ebersbach C; Department of Urology, Technische Universität Dresden, Dresden, Germany., Siciliano T; Department of Urology, Technische Universität Dresden, Dresden, Germany., Scholze J; Department of Urology, Technische Universität Dresden, Dresden, Germany., Hofmann J; Department of Urology, Technische Universität Dresden, Dresden, Germany., Hönscheid P; Institute of Pathology, Universitätsklinikum Carl Gustav Carus Dresden, 01307, Dresden, Germany.; National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany., Baretton GB; Institute of Pathology, Universitätsklinikum Carl Gustav Carus Dresden, 01307, Dresden, Germany.; National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany., Woods K; IIIrd Department of Medicine - Hematology & Oncology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany., Guezguez B; IIIrd Department of Medicine - Hematology & Oncology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany., Dubrovska A; OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.; Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, Dresden, Germany.; National Center for Tumor Diseases (NCT), Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.; German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Dresden, Germany., Markowitsch SD; Department of Urology and Pediatric Urology, University Medical Center Mainz, Mainz, Germany., Thomas C; Department of Urology, Technische Universität Dresden, Dresden, Germany.; National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany., Puhr M; Medical University of Innsbruck, Department of Urology, 6020, Innsbruck, Austria., Erb HHH; Department of Urology, Technische Universität Dresden, Dresden, Germany. holger.erb@uniklinikum-dresden.de.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2024 Jun; Vol. 43 (26), pp. 2038-2050. Date of Electronic Publication: 2024 May 15.
DOI: 10.1038/s41388-024-03059-4
Abstrakt: Docetaxel (DX) serves as a palliative treatment option for metastatic prostate cancer (PCa). Despite initial remission, acquired DX resistance is inevitable. The mechanisms behind DX resistance have not yet been deciphered, but a mesenchymal phenotype is associated with DX resistance. Mesenchymal phenotypes have been linked to metabolic rewiring, obtaining most ATP production by oxidative phosphorylation (OXPHOS) powered substantially by glutamine (Gln). Likewise, Gln is known to play an essential role in modulating bioenergetic, redox homeostasis and autophagy. Herein, investigations of Gln deprivation on DX-sensitive and -resistant (DR) PCa cells revealed that the DR cell sub-lines were susceptible to Gln deprivation. Mechanistically, Gln deprivation reduced OXPHOS and ATP levels, causing a disturbance in cell cycle progression. Genetic and chemical inhibition of the Gln-metabolism key protein GLS1 could validate the Gln deprivation results, thereby representing a valid therapeutic target. Moreover, immunohistological investigation of GLS1 revealed a high-expressing GLS1 subgroup post-docetaxel failure, exhibiting low overall survival. This subgroup presents an intriguing opportunity for targeted therapy focusing on glutamine metabolism. Thus, these findings highlight a possible clinical rationale for the chemical inhibition of GLS1 as a therapeutic strategy to target mesenchymal DR PCa cells, thereby delaying accelerated tumour progression.
(© 2024. The Author(s).)
Databáze: MEDLINE
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