2020
DOI: 10.1158/2159-8290.cd-20-1065
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Endogenous Retroelement Activation by Epigenetic Therapy Reverses the Warburg Effect and Elicits Mitochondrial-Mediated Cancer Cell Death

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 kil… Show more

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Cited by 48 publications
(30 citation statements)
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“…Our data suggest a role for different sensors in HSC activation. However, the role of MDA5 in haematopoietic regeneration may also depend on other functions besides its role in inducing inflammation, as activation of MDA5 has been associated with endoplasmic reticulum stress 50 , metabolism 51 and autophagy 52 .…”
Section: Discussionmentioning
confidence: 99%
“…Our data suggest a role for different sensors in HSC activation. However, the role of MDA5 in haematopoietic regeneration may also depend on other functions besides its role in inducing inflammation, as activation of MDA5 has been associated with endoplasmic reticulum stress 50 , metabolism 51 and autophagy 52 .…”
Section: Discussionmentioning
confidence: 99%
“…When cells are stimulated by external drugs, the level of ROS increases significantly and leads to the peroxidation of cell membrane proteins and lipids, causing the decrease in MMP, the increase in cell membrane permeability, and the release of a considerable number of free radicals and cytochrome C, and thus inducing cell apoptosis [ 77 ]. Apoptosis can be regulated by mitochondrial-mediated endogenous pathway [ 78 ]. Bcl-2 and Bax both belong to the Bcl-2 family; Bcl-2 belongs to anti-apoptotic gene, and Bax belongs to pro-apoptotic gene [ 79 ].…”
Section: Discussionmentioning
confidence: 99%
“…Epi-agents induce retroelements sensed by RIG-I and MDA5 which affect the intracellular glucose hydrolysis, resulting in energy depletion and tumor cell death. In addition, this effect is coupled with altered mitochondrial metabolism to compensate for ATP, and tumor cell death (necroptosis) is independent of caspase-mediated apoptosis but closely associated with BCL2 [ 107 ].…”
Section: Transposable Elementsmentioning
confidence: 99%