Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy

Objective: Cancer metabolic reprogramming promotes resistance to therapies. In this study, we addressed the role of the Warburg effect in the resistance to photodynamic therapy (PDT) in skin squamous cell carcinoma (sSCC). Furthermore, we assessed the effect of metformin treatment, an antidiabetic t...

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Autores: Mascaraque-Checa, Marta, Gallego-Rentero, María, Nicolás-Morala, Jimena, Portillo-Esnaola, Mikel, Cuezva, José M., González, Salvador, Gilaberte, Yolanda, Juarranz, Ángeles
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/370091
Acceso en línea:http://hdl.handle.net/10261/370091
Access Level:acceso abierto
Palabra clave:Skin squamous cell carcinoma
Cancer resistance
Photodynamic therapy
Warburg effectMetformin
AKT/mTOR pathway
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spelling Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapyMascaraque-Checa, MartaGallego-Rentero, MaríaNicolás-Morala, JimenaPortillo-Esnaola, MikelCuezva, José M.González, SalvadorGilaberte, YolandaJuarranz, ÁngelesSkin squamous cell carcinomaCancer resistancePhotodynamic therapyWarburg effectMetforminAKT/mTOR pathwayObjective: Cancer metabolic reprogramming promotes resistance to therapies. In this study, we addressed the role of the Warburg effect in the resistance to photodynamic therapy (PDT) in skin squamous cell carcinoma (sSCC). Furthermore, we assessed the effect of metformin treatment, an antidiabetic type II drug that modulates metabolism, as adjuvant to PDT. Methods: For that, we have used two human SCC cell lines: SCC13 and A431, called parental (P) and from these cell lines we have generated the corresponding PDT resistant cells (10GT). Results: Here, we show that 10GT cells induced metabolic reprogramming to an enhanced aerobic glycolysis and reduced activity of oxidative phosphorylation, which could influence the response to PDT. This result was also confirmed in P and 10GT SCC13 tumors developed in mice. The treatment with metformin caused a reduction in aerobic glycolysis and an increase in oxidative phosphorylation in 10GT sSCC cells. Finally, the combination of metformin with PDT improved the cytotoxic effects on P and 10GT cells. The combined treatment induced an increase in the protoporphyrin IX production, in the reactive oxygen species generation and in the AMPK expression and produced the inhibition of AKT/mTOR pathway. The greater efficacy of combined treatments was also seen in vivo, in xenografts of P and 10GT SCC13 cells. Conclusions: Altogether, our results reveal that PDT resistance implies, at least partially, a metabolic reprogramming towards aerobic glycolysis that is prevented by metformin treatment. Therefore, metformin may constitute an excellent adjuvant for PDT in sSCC.This research was supported by Spanish grants from Instituto de Salud Carlos III MINECO and Feder Funds (FIS PI15/00974; PI18/00858 and PI18/00708) and Ministerio de Ciencia, Innovación y Universidades (PID2019-108674RB-100).Instituto de Salud Carlos IIIMinisterio de Economía y Competitividad (España)European CommissionMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2024202420222024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/370091reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO//PI15%2F00974info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII)/PI18%2F00858info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII)/PI18%2F00708info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-108674RB-I00http://dx.doi.org/10.1016/j.molmet.2022.101496Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3700912026-05-22T06:33:51Z
dc.title.none.fl_str_mv Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy
title Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy
spellingShingle Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy
Mascaraque-Checa, Marta
Skin squamous cell carcinoma
Cancer resistance
Photodynamic therapy
Warburg effectMetformin
AKT/mTOR pathway
title_short Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy
title_full Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy
title_fullStr Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy
title_full_unstemmed Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy
title_sort Metformin overcomes metabolic reprogramming-induced resistance of skin squamous cell carcinoma to photodynamic therapy
dc.creator.none.fl_str_mv Mascaraque-Checa, Marta
Gallego-Rentero, María
Nicolás-Morala, Jimena
Portillo-Esnaola, Mikel
Cuezva, José M.
González, Salvador
Gilaberte, Yolanda
Juarranz, Ángeles
author Mascaraque-Checa, Marta
author_facet Mascaraque-Checa, Marta
Gallego-Rentero, María
Nicolás-Morala, Jimena
Portillo-Esnaola, Mikel
Cuezva, José M.
González, Salvador
Gilaberte, Yolanda
Juarranz, Ángeles
author_role author
author2 Gallego-Rentero, María
Nicolás-Morala, Jimena
Portillo-Esnaola, Mikel
Cuezva, José M.
González, Salvador
Gilaberte, Yolanda
Juarranz, Ángeles
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Ministerio de Economía y Competitividad (España)
European Commission
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Skin squamous cell carcinoma
Cancer resistance
Photodynamic therapy
Warburg effectMetformin
AKT/mTOR pathway
topic Skin squamous cell carcinoma
Cancer resistance
Photodynamic therapy
Warburg effectMetformin
AKT/mTOR pathway
description Objective: Cancer metabolic reprogramming promotes resistance to therapies. In this study, we addressed the role of the Warburg effect in the resistance to photodynamic therapy (PDT) in skin squamous cell carcinoma (sSCC). Furthermore, we assessed the effect of metformin treatment, an antidiabetic type II drug that modulates metabolism, as adjuvant to PDT. Methods: For that, we have used two human SCC cell lines: SCC13 and A431, called parental (P) and from these cell lines we have generated the corresponding PDT resistant cells (10GT). Results: Here, we show that 10GT cells induced metabolic reprogramming to an enhanced aerobic glycolysis and reduced activity of oxidative phosphorylation, which could influence the response to PDT. This result was also confirmed in P and 10GT SCC13 tumors developed in mice. The treatment with metformin caused a reduction in aerobic glycolysis and an increase in oxidative phosphorylation in 10GT sSCC cells. Finally, the combination of metformin with PDT improved the cytotoxic effects on P and 10GT cells. The combined treatment induced an increase in the protoporphyrin IX production, in the reactive oxygen species generation and in the AMPK expression and produced the inhibition of AKT/mTOR pathway. The greater efficacy of combined treatments was also seen in vivo, in xenografts of P and 10GT SCC13 cells. Conclusions: Altogether, our results reveal that PDT resistance implies, at least partially, a metabolic reprogramming towards aerobic glycolysis that is prevented by metformin treatment. Therefore, metformin may constitute an excellent adjuvant for PDT in sSCC.
publishDate 2022
dc.date.none.fl_str_mv 2022
2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/370091
url http://hdl.handle.net/10261/370091
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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#PLACEHOLDER_PARENT_METADATA_VALUE#
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info:eu-repo/grantAgreement/MINECO//PI15%2F00974
info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII)/PI18%2F00858
info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII)/PI18%2F00708
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-108674RB-I00
http://dx.doi.org/10.1016/j.molmet.2022.101496
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
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instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
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