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CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression
CD98 heavy chain (CD98hc) forms heteromeric amino acid (AA) transporters by interacting with different light chains. Cancer cells overexpress CD98hc-transporters in order to meet their increased nutritional and antioxidant demands, since they provide branched-chain AA (BCAA) and aromatic AA (AAA) av...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773781/ https://www.ncbi.nlm.nih.gov/pubmed/31575908 http://dx.doi.org/10.1038/s41598-019-50547-9 |
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author | Cano-Crespo, Sara Chillarón, Josep Junza, Alexandra Fernández-Miranda, Gonzalo García, Judit Polte, Christine R. de la Ballina, Laura Ignatova, Zoya Yanes, Óscar Zorzano, Antonio Stephan-Otto Attolini, Camille Palacín, Manuel |
author_facet | Cano-Crespo, Sara Chillarón, Josep Junza, Alexandra Fernández-Miranda, Gonzalo García, Judit Polte, Christine R. de la Ballina, Laura Ignatova, Zoya Yanes, Óscar Zorzano, Antonio Stephan-Otto Attolini, Camille Palacín, Manuel |
author_sort | Cano-Crespo, Sara |
collection | PubMed |
description | CD98 heavy chain (CD98hc) forms heteromeric amino acid (AA) transporters by interacting with different light chains. Cancer cells overexpress CD98hc-transporters in order to meet their increased nutritional and antioxidant demands, since they provide branched-chain AA (BCAA) and aromatic AA (AAA) availability while protecting cells from oxidative stress. Here we show that BCAA and AAA shortage phenocopies the inhibition of mTORC1 signalling, protein synthesis and cell proliferation caused by CD98hc ablation. Furthermore, our data indicate that CD98hc sustains glucose uptake and glycolysis, and, as a consequence, the pentose phosphate pathway (PPP). Thus, loss of CD98hc triggers a dramatic reduction in the nucleotide pool, which leads to replicative stress in these cells, as evidenced by the enhanced DNA Damage Response (DDR), S-phase delay and diminished rate of mitosis, all recovered by nucleoside supplementation. In addition, proper BCAA and AAA availability sustains the expression of the enzyme ribonucleotide reductase. In this regard, BCAA and AAA shortage results in decreased content of deoxynucleotides that triggers replicative stress, also recovered by nucleoside supplementation. On the basis of our findings, we conclude that CD98hc plays a central role in AA and glucose cellular nutrition, redox homeostasis and nucleotide availability, all key for cell proliferation. |
format | Online Article Text |
id | pubmed-6773781 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-67737812019-10-04 CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression Cano-Crespo, Sara Chillarón, Josep Junza, Alexandra Fernández-Miranda, Gonzalo García, Judit Polte, Christine R. de la Ballina, Laura Ignatova, Zoya Yanes, Óscar Zorzano, Antonio Stephan-Otto Attolini, Camille Palacín, Manuel Sci Rep Article CD98 heavy chain (CD98hc) forms heteromeric amino acid (AA) transporters by interacting with different light chains. Cancer cells overexpress CD98hc-transporters in order to meet their increased nutritional and antioxidant demands, since they provide branched-chain AA (BCAA) and aromatic AA (AAA) availability while protecting cells from oxidative stress. Here we show that BCAA and AAA shortage phenocopies the inhibition of mTORC1 signalling, protein synthesis and cell proliferation caused by CD98hc ablation. Furthermore, our data indicate that CD98hc sustains glucose uptake and glycolysis, and, as a consequence, the pentose phosphate pathway (PPP). Thus, loss of CD98hc triggers a dramatic reduction in the nucleotide pool, which leads to replicative stress in these cells, as evidenced by the enhanced DNA Damage Response (DDR), S-phase delay and diminished rate of mitosis, all recovered by nucleoside supplementation. In addition, proper BCAA and AAA availability sustains the expression of the enzyme ribonucleotide reductase. In this regard, BCAA and AAA shortage results in decreased content of deoxynucleotides that triggers replicative stress, also recovered by nucleoside supplementation. On the basis of our findings, we conclude that CD98hc plays a central role in AA and glucose cellular nutrition, redox homeostasis and nucleotide availability, all key for cell proliferation. Nature Publishing Group UK 2019-10-01 /pmc/articles/PMC6773781/ /pubmed/31575908 http://dx.doi.org/10.1038/s41598-019-50547-9 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Cano-Crespo, Sara Chillarón, Josep Junza, Alexandra Fernández-Miranda, Gonzalo García, Judit Polte, Christine R. de la Ballina, Laura Ignatova, Zoya Yanes, Óscar Zorzano, Antonio Stephan-Otto Attolini, Camille Palacín, Manuel CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression |
title | CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression |
title_full | CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression |
title_fullStr | CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression |
title_full_unstemmed | CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression |
title_short | CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression |
title_sort | cd98hc (slc3a2) sustains amino acid and nucleotide availability for cell cycle progression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773781/ https://www.ncbi.nlm.nih.gov/pubmed/31575908 http://dx.doi.org/10.1038/s41598-019-50547-9 |
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