Articles producció científica> Enginyeria Electrònica, Elèctrica i Automàtica

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

  • Identification data

    Identifier: imarina:6389895
    Authors:
    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
    Abstract:
    © 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.
  • Others:

    Author, as appears in the article.: 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
    Department: Enginyeria Electrònica, Elèctrica i Automàtica
    URV's Author/s: Junza Martínez, Alexandra / Yanes Torrado, Óscar
    Keywords: 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
    Abstract: © 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.
    Thematic Areas: Molecular medicine Medicine, research & experimental Medicina veterinaria Medicina ii Medicina i Farmacia Ciências biológicas iii Ciências biológicas ii Ciências biológicas i
    licence for use: https://creativecommons.org/licenses/by/3.0/es/
    ISSN: 1757-4676
    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.embopress.org/doi/full/10.15252/emmm.201911217
    Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
    Papper original source: Embo Molecular Medicine. 12 (e11217): e11217-
    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
    Article's DOI: 10.15252/emmm.201911217
    Entity: Universitat Rovira i Virgili
    Journal publication year: 2020
    Publication Type: Journal Publications
  • Keywords:

    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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