The redox state of cytochrome c modulates resistance to methotrexate in human MCF7 breast cancer cells.

<h4>Background</h4>Methotrexate is a chemotherapeutic agent used to treat a variety of cancers. However, the occurrence of resistance limits its effectiveness. Cytochrome c in its reduced state is less capable of triggering the apoptotic cascade. Thus, we set up to study the relationship...

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Autores principales:	Susana Barros, Núria Mencia, Laura Rodríguez, Carlota Oleaga, Conceição Santos, Verónique Noé, Carlos J Ciudad
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/290a7a44e3a7489390dae166c1043b02
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spelling	oai:doaj.org-article:290a7a44e3a7489390dae166c1043b022021-11-18T07:45:59ZThe redox state of cytochrome c modulates resistance to methotrexate in human MCF7 breast cancer cells.1932-620310.1371/journal.pone.0063276https://doaj.org/article/290a7a44e3a7489390dae166c1043b022013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23675469/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Methotrexate is a chemotherapeutic agent used to treat a variety of cancers. However, the occurrence of resistance limits its effectiveness. Cytochrome c in its reduced state is less capable of triggering the apoptotic cascade. Thus, we set up to study the relationship among redox state of cytochrome c, apoptosis and the development of resistance to methotrexate in MCF7 human breast cancer cells.<h4>Results</h4>Cell incubation with cytochrome c-reducing agents, such as tetramethylphenylenediamine, ascorbate or reduced glutathione, decreased the mortality and apoptosis triggered by methotrexate. Conversely, depletion of glutathione increased the apoptotic action of methotrexate, showing an involvement of cytochrome c redox state in methotrexate-induced apoptosis. Methotrexate-resistant MCF7 cells showed increased levels of endogenous reduced glutathione and a higher capability to reduce exogenous cytochrome c. Using functional genomics we detected the overexpression of GSTM1 and GSTM4 in methotrexate-resistant MCF7 breast cancer cells, and determined that methotrexate was susceptible of glutathionylation by GSTs. The inhibition of these GSTM isoforms caused an increase in methotrexate cytotoxicity in sensitive and resistant cells.<h4>Conclusions</h4>We conclude that overexpression of specific GSTMs, GSTM1 and GSTM4, together with increased endogenous reduced glutathione levels help to maintain a more reduced state of cytochrome c which, in turn, would decrease apoptosis, thus contributing to methotrexate resistance in human MCF7 breast cancer cells.Susana BarrosNúria MenciaLaura RodríguezCarlota OleagaConceição SantosVerónique NoéCarlos J CiudadPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e63276 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Susana Barros Núria Mencia Laura Rodríguez Carlota Oleaga Conceição Santos Verónique Noé Carlos J Ciudad The redox state of cytochrome c modulates resistance to methotrexate in human MCF7 breast cancer cells.
description	<h4>Background</h4>Methotrexate is a chemotherapeutic agent used to treat a variety of cancers. However, the occurrence of resistance limits its effectiveness. Cytochrome c in its reduced state is less capable of triggering the apoptotic cascade. Thus, we set up to study the relationship among redox state of cytochrome c, apoptosis and the development of resistance to methotrexate in MCF7 human breast cancer cells.<h4>Results</h4>Cell incubation with cytochrome c-reducing agents, such as tetramethylphenylenediamine, ascorbate or reduced glutathione, decreased the mortality and apoptosis triggered by methotrexate. Conversely, depletion of glutathione increased the apoptotic action of methotrexate, showing an involvement of cytochrome c redox state in methotrexate-induced apoptosis. Methotrexate-resistant MCF7 cells showed increased levels of endogenous reduced glutathione and a higher capability to reduce exogenous cytochrome c. Using functional genomics we detected the overexpression of GSTM1 and GSTM4 in methotrexate-resistant MCF7 breast cancer cells, and determined that methotrexate was susceptible of glutathionylation by GSTs. The inhibition of these GSTM isoforms caused an increase in methotrexate cytotoxicity in sensitive and resistant cells.<h4>Conclusions</h4>We conclude that overexpression of specific GSTMs, GSTM1 and GSTM4, together with increased endogenous reduced glutathione levels help to maintain a more reduced state of cytochrome c which, in turn, would decrease apoptosis, thus contributing to methotrexate resistance in human MCF7 breast cancer cells.
format	article
author	Susana Barros Núria Mencia Laura Rodríguez Carlota Oleaga Conceição Santos Verónique Noé Carlos J Ciudad
author_facet	Susana Barros Núria Mencia Laura Rodríguez Carlota Oleaga Conceição Santos Verónique Noé Carlos J Ciudad
author_sort	Susana Barros
title	The redox state of cytochrome c modulates resistance to methotrexate in human MCF7 breast cancer cells.
title_short	The redox state of cytochrome c modulates resistance to methotrexate in human MCF7 breast cancer cells.
title_full	The redox state of cytochrome c modulates resistance to methotrexate in human MCF7 breast cancer cells.
title_fullStr	The redox state of cytochrome c modulates resistance to methotrexate in human MCF7 breast cancer cells.
title_full_unstemmed	The redox state of cytochrome c modulates resistance to methotrexate in human MCF7 breast cancer cells.
title_sort	redox state of cytochrome c modulates resistance to methotrexate in human mcf7 breast cancer cells.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/290a7a44e3a7489390dae166c1043b02
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The redox state of cytochrome c modulates resistance to methotrexate in human MCF7 breast cancer cells.

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