| Title: |
Endogenous Retroelement Activation by Epigenetic Therapy Reverses the Warburg Effect and Elicits Mitochondrial-Mediated Cancer Cell Death |
| Authors: |
Universitat Rovira i Virgili; 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. |
| Source: |
Cancer Discovery; 10.1158/2159-8290.CD-20-1065; Cancer Discovery. 11 (5): 1268-1285 |
| Publisher Information: |
2021 |
| Document Type: |
Electronic Resource |
| 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. |
| Index Terms: |
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; Medicina ii; Medicina i; General medicine; Ciências biológicas iii; Ciências biológicas ii; Ciências biológicas i; Journal Publications |
| URL: |
http://hdl.handle.net/20.500.11797/imarina9216845 |
| Availability: |
Open access content. Open access content; info:eu-repo/semantics/openAccess |
| Other Numbers: |
RIV oai:urv.cat:imarina:9216845; 1443574754 |
| Contributing Source: |
UNIVERSITAT ROVIRA I VIRGILI BIBLIOTECA; From OAIster®, provided by the OCLC Cooperative. |
| Accession Number: |
edsoai.on1443574754 |
| Database: |
OAIster |