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ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer

Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) mediates uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumour cells. Uptake of glutamine and subsequent glutaminolysis is critical for activation of the mTORC1 nutrient-sensing pathway, which regu...

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Autores principales: van Geldermalsen, M, Wang, Q, Nagarajah, R, Marshall, A D, Thoeng, A, Gao, D, Ritchie, W, Feng, Y, Bailey, C G, Deng, N, Harvey, K, Beith, J M, Selinger, C I, O'Toole, S A, Rasko, J E J, Holst, J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914826/
https://www.ncbi.nlm.nih.gov/pubmed/26455325
http://dx.doi.org/10.1038/onc.2015.381
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author van Geldermalsen, M
Wang, Q
Nagarajah, R
Marshall, A D
Thoeng, A
Gao, D
Ritchie, W
Feng, Y
Bailey, C G
Deng, N
Harvey, K
Beith, J M
Selinger, C I
O'Toole, S A
Rasko, J E J
Holst, J
author_facet van Geldermalsen, M
Wang, Q
Nagarajah, R
Marshall, A D
Thoeng, A
Gao, D
Ritchie, W
Feng, Y
Bailey, C G
Deng, N
Harvey, K
Beith, J M
Selinger, C I
O'Toole, S A
Rasko, J E J
Holst, J
author_sort van Geldermalsen, M
collection PubMed
description Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) mediates uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumour cells. Uptake of glutamine and subsequent glutaminolysis is critical for activation of the mTORC1 nutrient-sensing pathway, which regulates cell growth and protein translation in cancer cells. This is of particular interest in breast cancer, as glutamine dependence is increased in high-risk breast cancer subtypes. Pharmacological inhibitors of ASCT2-mediated transport significantly reduced glutamine uptake in human breast cancer cell lines, leading to the suppression of mTORC1 signalling, cell growth and cell cycle progression. Notably, these effects were subtype-dependent, with ASCT2 transport critical only for triple-negative (TN) basal-like breast cancer cell growth compared with minimal effects in luminal breast cancer cells. Both stable and inducible shRNA-mediated ASCT2 knockdown confirmed that inhibiting ASCT2 function was sufficient to prevent cellular proliferation and induce rapid cell death in TN basal-like breast cancer cells, but not in luminal cells. Using a bioluminescent orthotopic xenograft mouse model, ASCT2 expression was then shown to be necessary for both successful engraftment and growth of HCC1806 TN breast cancer cells in vivo. Lower tumoral expression of ASCT2 conferred a significant survival advantage in xenografted mice. These responses remained intact in primary breast cancers, where gene expression analysis showed high expression of ASCT2 and glutamine metabolism-related genes, including GLUL and GLS, in a cohort of 90 TN breast cancer patients, as well as correlations with the transcriptional regulators, MYC and ATF4. This study provides preclinical evidence for the feasibility of novel therapies exploiting ASCT2 transporter activity in breast cancer, particularly in the high-risk basal-like subgroup of TN breast cancer where there is not only high expression of ASCT2, but also a marked reliance on its activity for sustained cellular proliferation.
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spelling pubmed-49148262016-06-30 ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer van Geldermalsen, M Wang, Q Nagarajah, R Marshall, A D Thoeng, A Gao, D Ritchie, W Feng, Y Bailey, C G Deng, N Harvey, K Beith, J M Selinger, C I O'Toole, S A Rasko, J E J Holst, J Oncogene Short Communication Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) mediates uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumour cells. Uptake of glutamine and subsequent glutaminolysis is critical for activation of the mTORC1 nutrient-sensing pathway, which regulates cell growth and protein translation in cancer cells. This is of particular interest in breast cancer, as glutamine dependence is increased in high-risk breast cancer subtypes. Pharmacological inhibitors of ASCT2-mediated transport significantly reduced glutamine uptake in human breast cancer cell lines, leading to the suppression of mTORC1 signalling, cell growth and cell cycle progression. Notably, these effects were subtype-dependent, with ASCT2 transport critical only for triple-negative (TN) basal-like breast cancer cell growth compared with minimal effects in luminal breast cancer cells. Both stable and inducible shRNA-mediated ASCT2 knockdown confirmed that inhibiting ASCT2 function was sufficient to prevent cellular proliferation and induce rapid cell death in TN basal-like breast cancer cells, but not in luminal cells. Using a bioluminescent orthotopic xenograft mouse model, ASCT2 expression was then shown to be necessary for both successful engraftment and growth of HCC1806 TN breast cancer cells in vivo. Lower tumoral expression of ASCT2 conferred a significant survival advantage in xenografted mice. These responses remained intact in primary breast cancers, where gene expression analysis showed high expression of ASCT2 and glutamine metabolism-related genes, including GLUL and GLS, in a cohort of 90 TN breast cancer patients, as well as correlations with the transcriptional regulators, MYC and ATF4. This study provides preclinical evidence for the feasibility of novel therapies exploiting ASCT2 transporter activity in breast cancer, particularly in the high-risk basal-like subgroup of TN breast cancer where there is not only high expression of ASCT2, but also a marked reliance on its activity for sustained cellular proliferation. Nature Publishing Group 2016-06-16 2015-10-12 /pmc/articles/PMC4914826/ /pubmed/26455325 http://dx.doi.org/10.1038/onc.2015.381 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Short Communication
van Geldermalsen, M
Wang, Q
Nagarajah, R
Marshall, A D
Thoeng, A
Gao, D
Ritchie, W
Feng, Y
Bailey, C G
Deng, N
Harvey, K
Beith, J M
Selinger, C I
O'Toole, S A
Rasko, J E J
Holst, J
ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer
title ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer
title_full ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer
title_fullStr ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer
title_full_unstemmed ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer
title_short ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer
title_sort asct2/slc1a5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914826/
https://www.ncbi.nlm.nih.gov/pubmed/26455325
http://dx.doi.org/10.1038/onc.2015.381
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