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