Author, as appears in the article.: Cano-Crespo, Sara; Chillaron, Josep; Junza, Alexandra; Fernandez-Miranda, Gonzalo; Garcia, Judit; Polte, Christine; de la Ballina, Laura R; Ignatova, Zoya; Yanes, Oscar; Zorzano, Antonio; Stephan-Otto Attolini, Camille; Palacin, Manuel
Department: Enginyeria Electrònica, Elèctrica i Automàtica
URV's Author/s: Junza Martínez, Alexandra / Yanes Torrado, Óscar
Keywords: Therapeutic target Slc3a2 protein, human Replication stress Regulated eif2-alpha kinase Purine synthesis Oxidative stress Nutrient transporters Nucleotides Nasopharyngeal carcinoma Mechanistic target of rapamycin complex 1 Mammalian target Humans Glutamine-metabolism Gene knockout techniques Gene expression profiling Fusion regulatory protein 1, heavy chain Dna-damage response Dna repair Dna damage Cell division Cell cycle Amino acids, branched-chain Amino acids, aromatic Amino acids
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.
Thematic Areas: Zootecnia / recursos pesqueiros Saúde coletiva Química Psicología Odontología Nutrição Multidisciplinary sciences Multidisciplinary Medicina veterinaria Medicina iii Medicina ii Medicina i Materiais Matemática / probabilidade e estatística Letras / linguística Interdisciplinar Geografía Geociências Farmacia Engenharias iv Engenharias iii Engenharias ii Enfermagem Educação física Educação Economia Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciências ambientais Ciências agrárias i Ciência de alimentos Ciência da computação Biotecnología Biodiversidade Astronomia / física
licence for use: https://creativecommons.org/licenses/by/3.0/es/
ISSN: 20452322
Author's mail: oscar.yanes@urv.cat alexandra.junza@urv.cat
Author identifier: 0000-0003-3695-7157 0000-0001-7205-0419
Record's date: 2024-10-12
Papper version: info:eu-repo/semantics/publishedVersion
Link to the original source: https://www.nature.com/articles/s41598-019-50547-9
Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
Papper original source: Scientific Reports. 9 (1): 14065-14065
APA: Cano-Crespo, Sara; Chillaron, Josep; Junza, Alexandra; Fernandez-Miranda, Gonzalo; Garcia, Judit; Polte, Christine; de la Ballina, Laura R; Ignatova, (2019). CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression. Scientific Reports, 9(1), 14065-14065. DOI: 10.1038/s41598-019-50547-9
Article's DOI: 10.1038/s41598-019-50547-9
Entity: Universitat Rovira i Virgili
Journal publication year: 2019
Publication Type: Journal Publications
Repositori URV