dc.creator | Villanueva-Paz, Marina | es |
dc.creator | Cordero, Mario D. | es |
dc.creator | Pavón, Ana Delgado | es |
dc.creator | Castejón Vega, Beatriz | es |
dc.creator | Cotán, David | es |
dc.creator | De la Mata, Mario | es |
dc.creator | Oropesa-Ávila, Manuel | es |
dc.creator | Alcocer-Gómez, Elísabet | es |
dc.creator | Muntané Relat, Jordi | es |
dc.creator | Miguel Rodríguez, Manuel de | es |
dc.creator | Sánchez-Alcázar, José Antonio | es |
dc.date.accessioned | 2024-05-29T12:52:59Z | |
dc.date.available | 2024-05-29T12:52:59Z | |
dc.date.issued | 2016-08-07 | |
dc.identifier.citation | Villanueva-Paz, M., Cordero, M.D., Pavón, A.D., Castejón Vega, B., Cotán, D., De la Mata, M.,...,Sánchez-Alcázar, J.A. (2016). Amitriptyline induces mitophagy that precedes apoptosis in human HepG2 cells. Genes & Cancer, 7 (7-8), 260-277. https://doi.org/10.18632/genesandcancer.114. | |
dc.identifier.issn | 1947-6019 | es |
dc.identifier.uri | https://hdl.handle.net/11441/159444 | |
dc.description.abstract | Systemic treatments for hepatocellular carcinoma (HCC) have been largely
unsuccessful. This study investigated the antitumoral activity of Amitriptyline, a
tricyclic antidepressant, in hepatoma cells. Amitriptyline-induced toxicity involved
early mitophagy activation that subsequently switched to apoptosis. Amitriptyline
induced mitochondria dysfunction and oxidative stress in HepG2 cells. Amitriptyline
specifically inhibited mitochondrial complex III activity that is associated with
decreased mitochondrial membrane potential (∆Ψm) and increased reactive oxygen
species (ROS) production. Transmission electron microscopy (TEM) studies revealed
structurally abnormal mitochondria that were engulfed by double-membrane
structures resembling autophagosomes. Consistent with mitophagy activation,
fluorescence microscopy analysis showed mitochondrial Parkin recruitment and
colocalization of mitochondria with autophagosome protein markers.
Pharmacological or genetic inhibition of autophagy exacerbated the deleterious
effects of Amitriptyline on hepatoma cells and led to increased apoptosis. These
results suggest that mitophagy acts as an initial adaptive mechanism of cell survival.
However persistent mitochondrial damage induced extensive and lethal mitophagy,
autophagy stress and autophagolysome permeabilization leading eventually to cell
death by apoptosis. Amitriptyline also induced cell death in hepatoma cells lines with
mutated p53 and non-sense p53 mutation.
Our results support the hypothesis that Amitriptyline-induced mitochondrial
dysfunction can be a useful therapeutic strategy for HCC treatment, especially in
tumors showing p53 mutations and/or resistant to genotoxic treatments. | es |
dc.format | application/pdf | es |
dc.format.extent | 18 p. | es |
dc.language.iso | eng | es |
dc.relation.ispartof | Genes & Cancer, 7 (7-8), 260-277. | |
dc.rights | Atribución 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject | Mitophagy | es |
dc.subject | Apoptosis | es |
dc.subject | Amitriptyline | es |
dc.subject | Oxidative stress | es |
dc.subject | HepG2 cells | es |
dc.title | Amitriptyline induces mitophagy that precedes apoptosis in human HepG2 cells | es |
dc.type | info:eu-repo/semantics/article | es |
dc.type.version | info:eu-repo/semantics/publishedVersion | es |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Citología e Histología Normal y Patológica | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Psicología Experimental | es |
dc.relation.publisherversion | https://www.genesandcancer.com/article/114/text/ | es |
dc.identifier.doi | 10.18632/genesandcancer.114 | es |
dc.journaltitle | Genes & Cancer | es |
dc.publication.volumen | 7 | es |
dc.publication.issue | 7-8 | es |
dc.publication.initialPage | 260 | es |
dc.publication.endPage | 277 | es |