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Ablation of the ASCT2 (SLC1A5) gene encoding a neutral amino acid transporter reveals transporter plasticity and redundancy in cancer cells.
Bröer, Angelika; Gauthier-Coles, Gregory; Rahimi, Farid; van Geldermalsen, Michelle; Dorsch, Dieter; Wegener, Ansgar; Holst, Jeff; Bröer, Stefan.
Afiliación
  • Bröer A; From the Research School of Biology, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
  • Gauthier-Coles G; From the Research School of Biology, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
  • Rahimi F; From the Research School of Biology, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
  • van Geldermalsen M; Origins of Cancer Program, Centenary Institute, University of Sydney, Sydney, New South Wales 2050, Australia.
  • Dorsch D; Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.
  • Wegener A; Merck KGaA, 64293 Darmstadt, Germany, and.
  • Holst J; Merck KGaA, 64293 Darmstadt, Germany, and.
  • Bröer S; School of Medical Sciences and Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
J Biol Chem ; 294(11): 4012-4026, 2019 03 15.
Article en En | MEDLINE | ID: mdl-30635397
The neutral amino acid transporter solute carrier family 1 member 5 (SLC1A5 or ASCT2) is overexpressed in many cancers. To identify its roles in tumors, we employed 143B osteosarcoma cells and HCC1806 triple-negative breast cancer cells with or without ASCT2 deletion. ASCT2ko 143B cells grew well in standard culture media, but ASCT2 was required for optimal growth at <0.5 mm glutamine, with tumor spheroid growth and monolayer migration of 143B ASCT2ko cells being strongly impaired at lower glutamine concentrations. However, the ASCT2 deletion did not affect matrix-dependent invasion. ASCT2ko 143B xenografts in nude mice exhibited a slower onset of growth and a higher number of small tumors than ASCT2wt 143B xenografts, but did not differ in average tumor size 25 days after xenotransplantation. ASCT2 deficiency was compensated by increased levels of sodium neutral amino acid transporter 1 (SNAT1 or SLC38A1) and SNAT2 (SLC38A2) in ASCT2ko 143B cells, mediated by a GCN2 EIF2α kinase (GCN2)-dependent pathway, but this compensation was not observed in ASCT2ko HCC1806 cells. Combined SNAT1 silencing and GCN2 inhibition significantly inhibited growth of ASCT2ko HCC1806 cells, but not of ASCT2ko 143B cells. Similarly, pharmacological inhibition of l-type amino acid transporter 1 (LAT1) and GCN2 significantly inhibited growth of ASCT2ko HCC1806 cells, but not of ASCT2ko 143B cells. We conclude that cancer cells with reduced transporter plasticity are more vulnerable to disruption of amino acid homeostasis than cells with a full capacity to up-regulate redundant transporters by an integrated stress response.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Óseas / Neoplasias de la Mama / Osteosarcoma / Antígenos de Histocompatibilidad Menor / Sistema de Transporte de Aminoácidos ASC Límite: Animals / Female / Humans Idioma: En Revista: J Biol Chem Año: 2019 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Óseas / Neoplasias de la Mama / Osteosarcoma / Antígenos de Histocompatibilidad Menor / Sistema de Transporte de Aminoácidos ASC Límite: Animals / Female / Humans Idioma: En Revista: J Biol Chem Año: 2019 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos