Autor según el artículo: Cano-Crespo S, Chillarón J, Junza A, Fernández-Miranda G, García J, Polte C, R de la Ballina L, Ignatova Z, Yanes Ó, Zorzano A, Stephan-Otto Attolini C, Palacín M

Departamento: Enginyeria Electrònica, Elèctrica i Automàtica

Autor/es de la URV: Junza Martínez, Alexandra / Yanes Torrado, Óscar

Palabras clave: Therapeutic target Replication stress Regulated eif2-alpha kinase Purine synthesis Oxidative stress Nutrient transporters Nasopharyngeal carcinoma Mammalian target Glutamine-metabolism Dna-damage response

Resumen: 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.

Áreas temáticas: 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

Acceso a la licencia de uso: https://creativecommons.org/licenses/by/3.0/es/

ISSN: 20452322

Direcció de correo del autor: alexandra.junza@urv.cat oscar.yanes@urv.cat

Identificador del autor: 0000-0001-7205-0419 0000-0003-3695-7157

Fecha de alta del registro: 2023-02-22

Versión del articulo depositado: info:eu-repo/semantics/publishedVersion

Enlace a la fuente original: https://www.nature.com/articles/s41598-019-50547-9

URL Documento de licencia: http://repositori.urv.cat/ca/proteccio-de-dades/

Referencia al articulo segun fuente origial: Scientific Reports. 9 (1): 14065-14065

Referencia de l'ítem segons les normes APA: Cano-Crespo S, Chillarón J, Junza A, Fernández-Miranda G, García J, Polte C, R de la Ballina L, Ignatova Z, Yanes Ó, Zorzano A, Stephan-Otto Attolini (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

DOI del artículo: 10.1038/s41598-019-50547-9

Entidad: Universitat Rovira i Virgili

Año de publicación de la revista: 2019

Tipo de publicación: Journal Publications