Articles producció científica> Enginyeria Electrònica, Elèctrica i Automàtica

Endogenous Retroelement Activation by Epigenetic Therapy Reverses the Warburg Effect and Elicits Mitochondrial-Mediated Cancer Cell Death

  • Identification data

    Identifier: imarina:9216845
    Authors:
    Fresquet, VicenteGarcia-Barchino, Maria JLarrayoz, MartaCelay, JonVicente, CarmenFernandez-Galilea, MartaLarrayoz, Maria JCalasanz, Maria JPanizo, CarlosJunza, AlexandraHan, JiahuaiPrior, CeliaFortes, PuriPio, RubenOyarzabal, JulenMartinez-Baztan, AlvaroPaiva, BrunoMoreno-Aliaga, Maria JOdero, Maria DAgirre, XabierYanes, OscarProsper, FelipeMartinez-Climent, Jose A
    Abstract:
    For millions of years, endogenous retroelements have remained transcriptionally silent within mammalian genomes by epigenetic mechanisms. Modern anticancer therapies targeting the epigenetic machinery awaken retroelement expression, inducing antiviral responses that eliminate tumors through mechanisms not completely understood. Here, we find that massive binding of epigenetically activated retroelements by RIG-I and MDA5 viral sensors promotes ATP hydrolysis and depletes intracellular energy, driving tumor killing independently of immune signaling. Energy depletion boosts compensatory ATP production by switching glycolysis to mitochondrial oxidative phosphorylation, thereby reversing the Warburg effect. However, hyperfunctional succinate dehydrogenase in mitochondrial electron transport chain generates excessive oxidative stress that unleashes RIP1-mediated necroptosis. To maintain ATP generation, hyperactive mitochondrial membrane blocks intrinsic apoptosis by increasing BCL2 dependency. Accordingly, drugs targeting BCL2 family proteins and epigenetic inhibitors yield synergistic responses in multiple cancer types. Thus, epigenetic therapy kills cancer cells by rewiring mitochondrial metabolism upon retroelement activation, which primes mitochondria to apoptosis by BH3-mimetics. SIGNIFICANCE: The state of viral mimicry induced by epigenetic therapies in cancer cells remodels mitochondrial metabolism and drives caspase-independent tumor cell death, which sensitizes to BCL2 inhibitor drugs. This novel mechanism underlies clinical efficacy of hypomethylating agents and venetoclax in acute myeloid leukemia, suggesting similar combination therapies for other incurable cancers.
  • Others:

    Author, as appears in the article.: Fresquet, Vicente; Garcia-Barchino, Maria J; Larrayoz, Marta; Celay, Jon; Vicente, Carmen; Fernandez-Galilea, Marta; Larrayoz, Maria J; Calasanz, Maria J; Panizo, Carlos; Junza, Alexandra; Han, Jiahuai; Prior, Celia; Fortes, Puri; Pio, Ruben; Oyarzabal, Julen; Martinez-Baztan, Alvaro; Paiva, Bruno; Moreno-Aliaga, Maria J; Odero, Maria D; Agirre, Xabier; Yanes, Oscar; Prosper, Felipe; Martinez-Climent, Jose A
    Department: Enginyeria Electrònica, Elèctrica i Automàtica
    URV's Author/s: Junza Martínez, Alexandra / Yanes Torrado, Óscar
    Keywords: Western blotting Warburg effect Vorinostat Venetoclax Ubiquitination Transmission electron microscopy Target Synergistic effect Switch Succinate dehydrogenase Sensitivity Rip3 Rig-i Retroposon Retinoic acid inducible protein i Real time polymerase chain reaction Reactive oxygen metabolite Protein phosphorylation Protein bcl 2 Primary cell Oxidative stress Oxidative phosphorylation Nonhuman Multiple cancer Mouse Mitochondrial respiration Mitochondrial membrane potential Mitochondrial membrane Mitochondrial energy transfer Metabolic flux analysis Mda5 Mass spectrometry Mass fragmentography Isobutylene Interferon response Interferon regulatory factor 7 Interferon induced helicase c domain containing protein 1 Inhibitor Immunofluorescence Immune signaling Human cell Human Histone deacetylase inhibitor Histone deacetylase Glutamic acid Glutamate dehydrogenase Glucose transporter 4 Glucose oxidation Flow cytometry Female Fatty acid oxidation Epigenetics Drug targeting Dna methyltransferase Cytotoxicity Cytochrome c oxidase Crispr cas system Controlled study Citric acid cycle Cell viability Cell proliferation Cell energy Cell death Caspase 3 Caspase Cancer cell Bcl-2 Article Apoptosis Antineoplastic agent Antineoplastic activity Animal experiment Agar gel electrophoresis Adenosine triphosphate
    Abstract: For millions of years, endogenous retroelements have remained transcriptionally silent within mammalian genomes by epigenetic mechanisms. Modern anticancer therapies targeting the epigenetic machinery awaken retroelement expression, inducing antiviral responses that eliminate tumors through mechanisms not completely understood. Here, we find that massive binding of epigenetically activated retroelements by RIG-I and MDA5 viral sensors promotes ATP hydrolysis and depletes intracellular energy, driving tumor killing independently of immune signaling. Energy depletion boosts compensatory ATP production by switching glycolysis to mitochondrial oxidative phosphorylation, thereby reversing the Warburg effect. However, hyperfunctional succinate dehydrogenase in mitochondrial electron transport chain generates excessive oxidative stress that unleashes RIP1-mediated necroptosis. To maintain ATP generation, hyperactive mitochondrial membrane blocks intrinsic apoptosis by increasing BCL2 dependency. Accordingly, drugs targeting BCL2 family proteins and epigenetic inhibitors yield synergistic responses in multiple cancer types. Thus, epigenetic therapy kills cancer cells by rewiring mitochondrial metabolism upon retroelement activation, which primes mitochondria to apoptosis by BH3-mimetics. SIGNIFICANCE: The state of viral mimicry induced by epigenetic therapies in cancer cells remodels mitochondrial metabolism and drives caspase-independent tumor cell death, which sensitizes to BCL2 inhibitor drugs. This novel mechanism underlies clinical efficacy of hypomethylating agents and venetoclax in acute myeloid leukemia, suggesting similar combination therapies for other incurable cancers.
    Thematic Areas: Oncology Medicina ii Medicina i General medicine Ciências biológicas iii Ciências biológicas ii Ciências biológicas i
    licence for use: https://creativecommons.org/licenses/by/3.0/es/
    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://aacrjournals.org/cancerdiscovery/article/11/5/1268/666339/Endogenous-Retroelement-Activation-by-Epigenetic
    Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
    Papper original source: Cancer Discovery. 11 (5): 1268-1285
    APA: Fresquet, Vicente; Garcia-Barchino, Maria J; Larrayoz, Marta; Celay, Jon; Vicente, Carmen; Fernandez-Galilea, Marta; Larrayoz, Maria J; Calasanz, Mari (2021). Endogenous Retroelement Activation by Epigenetic Therapy Reverses the Warburg Effect and Elicits Mitochondrial-Mediated Cancer Cell Death. Cancer Discovery, 11(5), 1268-1285. DOI: 10.1158/2159-8290.CD-20-1065
    Article's DOI: 10.1158/2159-8290.CD-20-1065
    Entity: Universitat Rovira i Virgili
    Journal publication year: 2021
    Publication Type: Journal Publications
  • Keywords:

    Oncology
    Western blotting
    Warburg effect
    Vorinostat
    Venetoclax
    Ubiquitination
    Transmission electron microscopy
    Target
    Synergistic effect
    Switch
    Succinate dehydrogenase
    Sensitivity
    Rip3
    Rig-i
    Retroposon
    Retinoic acid inducible protein i
    Real time polymerase chain reaction
    Reactive oxygen metabolite
    Protein phosphorylation
    Protein bcl 2
    Primary cell
    Oxidative stress
    Oxidative phosphorylation
    Nonhuman
    Multiple cancer
    Mouse
    Mitochondrial respiration
    Mitochondrial membrane potential
    Mitochondrial membrane
    Mitochondrial energy transfer
    Metabolic flux analysis
    Mda5
    Mass spectrometry
    Mass fragmentography
    Isobutylene
    Interferon response
    Interferon regulatory factor 7
    Interferon induced helicase c domain containing protein 1
    Inhibitor
    Immunofluorescence
    Immune signaling
    Human cell
    Human
    Histone deacetylase inhibitor
    Histone deacetylase
    Glutamic acid
    Glutamate dehydrogenase
    Glucose transporter 4
    Glucose oxidation
    Flow cytometry
    Female
    Fatty acid oxidation
    Epigenetics
    Drug targeting
    Dna methyltransferase
    Cytotoxicity
    Cytochrome c oxidase
    Crispr cas system
    Controlled study
    Citric acid cycle
    Cell viability
    Cell proliferation
    Cell energy
    Cell death
    Caspase 3
    Caspase
    Cancer cell
    Bcl-2
    Article
    Apoptosis
    Antineoplastic agent
    Antineoplastic activity
    Animal experiment
    Agar gel electrophoresis
    Adenosine triphosphate
    Oncology
    Medicina ii
    Medicina i
    General medicine
    Ciências biológicas iii
    Ciências biológicas ii
    Ciências biológicas i
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