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Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development.
Wang, Qian; Hardie, Rae-Anne; Hoy, Andrew J; van Geldermalsen, Michelle; Gao, Dadi; Fazli, Ladan; Sadowski, Martin C; Balaban, Seher; Schreuder, Mark; Nagarajah, Rajini; Wong, Justin J-L; Metierre, Cynthia; Pinello, Natalia; Otte, Nicholas J; Lehman, Melanie L; Gleave, Martin; Nelson, Colleen C; Bailey, Charles G; Ritchie, William; Rasko, John E J; Holst, Jeff.
Afiliação
  • Wang Q; Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW, Australia.
  • Hardie RA; Sydney Medical School, University of Sydney, NSW, Australia.
  • Hoy AJ; Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
  • van Geldermalsen M; Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW, Australia.
  • Gao D; Sydney Medical School, University of Sydney, NSW, Australia.
  • Fazli L; Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
  • Sadowski MC; Discipline of Physiology, Bosch Institute and Charles Perkins Centre, University of Sydney, NSW, Australia.
  • Balaban S; Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW, Australia.
  • Schreuder M; Sydney Medical School, University of Sydney, NSW, Australia.
  • Nagarajah R; Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
  • Wong JJ; Sydney Medical School, University of Sydney, NSW, Australia.
  • Metierre C; Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
  • Pinello N; Bioinformatics, Centenary Institute, Camperdown, NSW, Australia.
  • Otte NJ; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
  • Lehman ML; Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Australia.
  • Gleave M; Discipline of Physiology, Bosch Institute and Charles Perkins Centre, University of Sydney, NSW, Australia.
  • Nelson CC; Discipline of Physiology, Bosch Institute and Charles Perkins Centre, University of Sydney, NSW, Australia.
  • Bailey CG; Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW, Australia.
  • Ritchie W; Sydney Medical School, University of Sydney, NSW, Australia.
  • Rasko JE; Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
  • Holst J; Sydney Medical School, University of Sydney, NSW, Australia.
J Pathol ; 236(3): 278-89, 2015 Jul.
Article em En | MEDLINE | ID: mdl-25693838
ABSTRACT
Glutamine is conditionally essential in cancer cells, being utilized as a carbon and nitrogen source for macromolecule production, as well as for anaplerotic reactions fuelling the tricarboxylic acid (TCA) cycle. In this study, we demonstrated that the glutamine transporter ASCT2 (SLC1A5) is highly expressed in prostate cancer patient samples. Using LNCaP and PC-3 prostate cancer cell lines, we showed that chemical or shRNA-mediated inhibition of ASCT2 function in vitro decreases glutamine uptake, cell cycle progression through E2F transcription factors, mTORC1 pathway activation and cell growth. Chemical inhibition also reduces basal oxygen consumption and fatty acid synthesis, showing that downstream metabolic function is reliant on ASCT2-mediated glutamine uptake. Furthermore, shRNA knockdown of ASCT2 in PC-3 cell xenografts significantly inhibits tumour growth and metastasis in vivo, associated with the down-regulation of E2F cell cycle pathway proteins. In conclusion, ASCT2-mediated glutamine uptake is essential for multiple pathways regulating the cell cycle and cell growth, and is therefore a putative therapeutic target in prostate cancer.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / Regulação Neoplásica da Expressão Gênica / Sistema ASC de Transporte de Aminoácidos / Glutamina Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2015 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / Regulação Neoplásica da Expressão Gênica / Sistema ASC de Transporte de Aminoácidos / Glutamina Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2015 Tipo de documento: Article