Autor según el artículo: Lahiguera Á., Hyroššová P., Figueras A., Garzón D., Moreno R., Soto-Cerrato V., McNeish I., Serra V., Lazaro C., Barretina P., Brunet J., Menéndez J., Matias-Guiu X., Vidal A., Villanueva A., Taylor-Harding B., Tanaka H., Orsulic S., Junza A., Yanes O., Muñoz-Pinedo C., Palomero L., Pujana M.À., Perales J.C., Viñals F.

Departamento: Enginyeria Electrònica, Elèctrica i Automàtica

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

Palabras clave: Stem-cells Risk Resistance Proliferation Parp inhibitors Oxphos Mutations Metformin Dna-damage response Diabetic-patients Chemotherapy Cancer-cell sensitivity Cancer metabolism Bcra parp inhibitors cancer metabolism oxphos bcra

Resumen: © 2020 The Authors. Published under the terms of the CC BY 4.0 license Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination-defective (HRD) cancers rely on oxidative metabolism to supply NAD+ and ATP for poly(ADP-ribose) polymerase (PARP)-dependent DNA repair mechanisms. Studies in breast and ovarian cancer HRD models depict a metabolic shift that includes enhanced expression of the oxidative phosphorylation (OXPHOS) pathway and its key components and a decline in the glycolytic Warburg phenotype. Hence, HRD cells are more sensitive to metformin and NAD+ concentration changes. On the other hand, shifting from an OXPHOS to a highly glycolytic metabolism interferes with the sensitivity to PARP inhibitors (PARPi) in these HRD cells. This feature is associated with a weak response to PARP inhibition in patient-derived xenografts, emerging as a new mechanism to determine PARPi sensitivity. This study shows a mechanistic link between two major cancer hallmarks, which in turn suggests novel possibilities for specifically treating HRD cancers with OXPHOS inhibitors.

Áreas temáticas: Molecular medicine Medicine, research & experimental Medicina veterinaria Medicina ii Medicina i Farmacia Ciências biológicas iii Ciências biológicas ii Ciências biológicas i

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

ISSN: 1757-4676

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: 2023-02-26

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

Enlace a la fuente original: https://www.embopress.org/doi/full/10.15252/emmm.201911217

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

Referencia al articulo segun fuente origial: Embo Molecular Medicine. 12 (e11217): e11217-

Referencia de l'ítem segons les normes APA: Lahiguera Á., Hyroššová P., Figueras A., Garzón D., Moreno R., Soto-Cerrato V., McNeish I., Serra V., Lazaro C., Barretina P., Brunet J., Menéndez J., (2020). Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors. Embo Molecular Medicine, 12(e11217), e11217-. DOI: 10.15252/emmm.201911217

DOI del artículo: 10.15252/emmm.201911217

Entidad: Universitat Rovira i Virgili

Año de publicación de la revista: 2020

Tipo de publicación: Journal Publications