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Inhibition of guanosine monophosphate synthetase (GMPS) blocks glutamine metabolism and prostate cancer growth.
Wang, Qian; Guan, Yi Fang; Hancock, Sarah E; Wahi, Kanu; van Geldermalsen, Michelle; Zhang, Blake K; Pang, Angel; Nagarajah, Rajini; Mak, Blossom; Freidman, Natasha; Horvath, Lisa G; Turner, Nigel; Holst, Jeff.
Afiliación
  • Wang Q; Translational Cancer Metabolism Laboratory, School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney, Sydney, Australia.
  • Guan YF; Translational Cancer Metabolism Laboratory, School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney, Sydney, Australia.
  • Hancock SE; Mitochondrial Bioenergetics Laboratory, Department of Pharmacology, School of Medical Sciences, UNSW Sydney, Sydney, Australia.
  • Wahi K; Translational Cancer Metabolism Laboratory, School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney, Sydney, Australia.
  • van Geldermalsen M; Origins of Cancer Program, Centenary Institute, University of Sydney, Camperdown, Australia.
  • Zhang BK; Sydney Medical School, University of Sydney, Sydney, Australia.
  • Pang A; Origins of Cancer Program, Centenary Institute, University of Sydney, Camperdown, Australia.
  • Nagarajah R; Sydney Medical School, University of Sydney, Sydney, Australia.
  • Mak B; Translational Cancer Metabolism Laboratory, School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney, Sydney, Australia.
  • Freidman N; Origins of Cancer Program, Centenary Institute, University of Sydney, Camperdown, Australia.
  • Horvath LG; Sydney Medical School, University of Sydney, Sydney, Australia.
  • Turner N; Chris O'Brien Lifehouse, Sydney, Australia.
  • Holst J; Garvan Institute of Medical Research, Sydney, Australia.
J Pathol ; 254(2): 135-146, 2021 06.
Article en En | MEDLINE | ID: mdl-33768538
Glutamine is a critical nutrient in cancer; however, its contribution to purine metabolism in prostate cancer has not previously been determined. Guanosine monophosphate synthetase (GMPS) acts in the de novo purine biosynthesis pathway, utilizing a glutamine amide to synthesize the guanine nucleotide. This study demonstrates that GMPS mRNA expression correlates with Gleason score in prostate cancer samples, while high GMPS expression was associated with decreased rates of overall and disease/progression-free survival. Pharmacological inhibition or knockdown of GMPS significantly decreased cell growth in both LNCaP and PC-3 prostate cancer cells. We utilized [15 N-(amide)]glutamine and [U-13 C5 ]glutamine metabolomics to dissect the pathways involved and despite similar growth inhibition by GMPS knockdown, we show unique metabolic effects across each cell line. Using a PC-3 xenograft mouse model, tumor growth was also significantly decreased after GMPS knockdown, highlighting the importance of glutamine metabolism and providing support for GMPS as a therapeutic target in prostate cancer. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Ligasas de Carbono-Nitrógeno / Glutamina Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Humans / Male Idioma: En Revista: J Pathol Año: 2021 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Ligasas de Carbono-Nitrógeno / Glutamina Tipo de estudio: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Humans / Male Idioma: En Revista: J Pathol Año: 2021 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Reino Unido