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Title: Cd98hc (slc3A2) sustains amino acid and nucleotide availability for cell cycle progression
Author: Cano-Crespo, Sara
Chillarón Chaves, José Julio
Junza Martínez, Alexandra
Fernández-Miranda, Gonzalo
García Aymerich, Judith
Polte, Christine
Ballina, Laura R. de la
Ignatova, Zoya
Yanes, Oscar
Zorzano Olarte, Antonio
Stephan-Otto Attolini, Camille
Palacín Prieto, Manuel
Keywords: Aminoàcids
Cèl·lules canceroses
Amino acids
Cancer cells
Issue Date: 1-Oct-2019
Publisher: Nature Publishing Group
Abstract: 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.
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It is part of: Scientific Reports, 2019, vol. 9, p. 14065
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ISSN: 2045-2322
Appears in Collections:Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)

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