Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition

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dc.contributor.author Cruz-Bermúdez, Alberto
dc.contributor.author Laza-Briviesca, Raquel
dc.contributor.author Vicente-Blanco, Ramiro J.
dc.contributor.author García-Grande, Aránzazu
dc.contributor.author Coronado, Maria José
dc.contributor.author Laine-Menéndez, Sara
dc.contributor.author Palacios-Zambrano, Sara
dc.contributor.author Moreno-Villa, M. Rocío
dc.contributor.author Martín Ruiz-Valdepeñas, Asunción
dc.contributor.author Lendinez, Cristina
dc.contributor.author Romero, Atocha
dc.contributor.author Franco, Fernando
dc.contributor.author Calvo, Virginia
dc.contributor.author Alfaro, Cristina
dc.contributor.author Martín Acosta, Paloma
dc.contributor.author Salas, Clara
dc.contributor.author Garcia, José Miguel
dc.contributor.author Provencio, Mariano
dc.contributor.other UAM. Departamento de Anatomía Patológica es_ES
dc.contributor.other UAM. Departamento de Bioquímica es_ES
dc.contributor.other UAM. Departamento de Medicina es_ES
dc.contributor.other Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM) es_ES
dc.date.accessioned 2019-08-09T16:47:21Z
dc.date.available 2019-08-09T16:47:21Z
dc.date.issued 2019-05-14
dc.identifier.citation Free Radical Biology and Medicine 135 (2019): 167-181 es_ES
dc.identifier.issn 0891-5849 (print) es_ES
dc.identifier.issn 1873-4596 (online) es_ES
dc.identifier.uri http://hdl.handle.net/10486/688357
dc.description.abstract Background: Platinum-based chemotherapy remains the standard of care for most lung cancer cases. However chemoresistance is often developed during the treatment, limiting clinical utility of this drug. Recently, the ability of tumor cells to adapt their metabolism has been associated to resistance to therapies. In this study, we first described the metabolic reprogramming of Non-Small Cell Lung Cancer (NSCLC) in response to cisplatin treatment. Methods: Cisplatin-resistant versions of the A549, H1299, and H460 cell lines were generated by continuous drug exposure. The long-term metabolic changes, as well as, the early response to cisplatin treatment were analyzed in both, parental and cisplatin-resistant cell lines. In addition, four Patient-derived xenograft models treated with cisplatin along with paired pre- and post-treatment biopsies from patients were studied. Furthermore, metabolic targeting of these changes in cell lines was performed downregulating PGC-1α expression through siRNA or using OXPHOS inhibitors (metformin and rotenone). Results: Two out of three cisplatin-resistant cell lines showed a stable increase in mitochondrial function, PGC1-α and mitochondrial mass with reduced glycolisis, that did not affect the cell cycle. This phenomenon was confirmed in vivo. Post-treatment NSCLC tumors showed an increase in mitochondrial mass, PGC-1α and a decrease in the GAPDH/MT-CO1 ratio. In addition, we demonstrated how a ROS-mediated metabolism reprogramming, involving PGC-1α and increased mitochondrial mass, is induced during short-time cisplatin exposure. Moreover, we tested how cells with increased PGC-1a induced by ZLN005 treatment, showed reduced cisplatin-driven apoptosis. Remarkably, the long-term metabolic changes, as well as the metabolic reprogramming during short-time cisplatin exposure can be exploited as an Achilles’ heel of NSCLC cells, as demonstrated by the increased sensitivity to PGC-1α interference or OXPHOS inhibition using metformin or rotenone. Conclusion: These results describe a new cisplatin resistance mechanism in NSCLC based on a metabolic reprogramming that is therapeutically exploitable through PGC-1α downregulation or OXPHOS inhibitors. en_US
dc.description.sponsorship Work in the authors’ laboratories is supported by ‘‘Instituto de Salud Carlos III’’ PI13/01806 and PIE14/0064 to M.P. A.C-B, received a Spanish Lung Cancer Group fellowship. R.L-B, is supported by Comunidad Autónoma de Madrid “Garantía juvenil” contract en_US
dc.format.extent 15 págs. es_ES
dc.format.mimetype application/pdf en
dc.language.iso eng en
dc.publisher Elsevier Inc. es_ES
dc.relation.ispartof Free Radical Biology and Medicine es_ES
dc.rights © 2019 The Authors en_US
dc.subject.other Chemoresistance en_US
dc.subject.other Chemotherapy en_US
dc.subject.other Metabolism en_US
dc.subject.other Metformin en_US
dc.subject.other NSCLC en_US
dc.title Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition en_US
dc.type article en
dc.subject.eciencia Medicina es_ES
dc.relation.publisherversion https://doi.org/10.1016/j.freeradbiomed.2019.03.009 es_ES
dc.identifier.doi 10.1016/j.freeradbiomed.2019.03.009 es_ES
dc.identifier.publicationfirstpage 167 es_ES
dc.identifier.publicationissue 135 es_ES
dc.identifier.publicationlastpage 181 es_ES
dc.relation.projectID Gobierno de España. PI13/01806 es_ES
dc.relation.projectID Gobierno de España. PIE14/0064 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion en
dc.rights.cc Reconocimiento – NoComercial – SinObraDerivada es_ES
dc.rights.accessRights openAccess en
dc.authorUAM Provencio Pulla, Mariano (262376)
dc.authorUAM Salas Antón, Clara María (261172)
dc.authorUAM Palacios Zambrano, Sara (265072)


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