Articles producció científica> Enginyeria Electrònica, Elèctrica i Automàtica

Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors

  • Datos identificativos

    Identificador: imarina:6389895
    Autores:
    Lahiguera, AlvaroHyrossova, PetraFigueras, AgnesGarzon, DianaMoreno, RogerSoto-Cerrato, VanessaMcNeish, IainSerra, VioletaLazaro, ConxiBarretina, PilarBrunet, JoanMenendez, JavierMatias-Guiu, XavierVidal, AugustVillanueva, AlbertoTaylor-Harding, BarbieTanaka, HisashiOrsulic, SandraJunza, AlexandraYanes, OscarMunoz-Pinedo, CristinaPalomero, LuisAngel Pujana, MiquelCarlos Perales, JoseVinals, Francesc
    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.
  • Otros:

    Autor según el artículo: Lahiguera, Alvaro; Hyrossova, Petra; Figueras, Agnes; Garzon, Diana; Moreno, Roger; Soto-Cerrato, Vanessa; McNeish, Iain; Serra, Violeta; Lazaro, Conxi; Barretina, Pilar; Brunet, Joan; Menendez, Javier; Matias-Guiu, Xavier; Vidal, August; Villanueva, Alberto; Taylor-Harding, Barbie; Tanaka, Hisashi; Orsulic, Sandra; Junza, Alexandra; Yanes, Oscar; Munoz-Pinedo, Cristina; Palomero, Luis; Angel Pujana, Miquel; Carlos Perales, Jose; Vinals, Francesc
    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: oscar.yanes@urv.cat alexandra.junza@urv.cat
    Identificador del autor: 0000-0003-3695-7157 0000-0001-7205-0419
    Fecha de alta del registro: 2024-10-12
    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: https://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, Alvaro; Hyrossova, Petra; Figueras, Agnes; Garzon, Diana; Moreno, Roger; Soto-Cerrato, Vanessa; McNeish, Iain; Serra, Violeta; Lazaro, Conx (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
  • Palabras clave:

    Medicine, Research & Experimental,Molecular Medicine
    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
    Molecular medicine
    Medicine, research & experimental
    Medicina veterinaria
    Medicina ii
    Medicina i
    Farmacia
    Ciências biológicas iii
    Ciências biológicas ii
    Ciências biológicas i
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