Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/156737
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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1038/s41598-019-50547-9 |
It is part of: | Scientific Reports, 2019, vol. 9, p. 14065 |
URI: | http://hdl.handle.net/2445/156737 |
Related resource: | https://doi.org/10.1038/s41598-019-50547-9 |
ISSN: | 2045-2322 |
Appears in Collections: | Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia) |
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