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Methylseleninic acid promotes antitumour effects via nuclear FOXO3a translocation through Akt inhibition

2015-12Journal article Open access
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dc.contributor.authorTarrado-Castellarnau, Miriam
dc.contributor.authorCortes, Roldan
dc.contributor.authorZanuy, Miriam
dc.contributor.authorTarrago-Celada, Josep
dc.contributor.authorPolat, Ibrahim H.
dc.contributor.authorHill, Richard
dc.contributor.authorFan, Teresa W. M.
dc.contributor.authorLink, Wolfgang
dc.contributor.authorCascante, Marta
dc.date.accessioned2018-12-07T14:52:47Z
dc.date.available2018-12-07T14:52:47Z
dc.date.issued2015-12
dc.description.abstractSelenium supplement has been shown in clinical trials to reduce the risk of different cancers including lung carcinoma. Previous studies reported that the antiproliferative and pro-apoptotic activities of methylseleninic acid (MSA) in cancer cells could be mediated by inhibition of the PI3K pathway. A better understanding of the downstream cellular targets of MSA will provide information on its mechanism of action and will help to optimize its use in combination therapies with PI3K inhibitors. For this study, the effects of MSA on viability, cell cycle, metabolism, apoptosis, protein and mRNA expression, and reactive oxygen species production were analysed in A549 cells. FOXO3a subcellular localization was examined in A549 cells and in stably transfected human osteosarcoma U2foxRELOC cells. Our results demonstrate that MSA induces FOXO3a nuclear translocation in A549 cells and in U2OS cells that stably express GFP-FOXO3a. Interestingly, sodium selenite, another selenium compound, did not induce any significant effects on FOXO3a translocation despite inducing apoptosis. Single strand break of DNA, disruption of tumour cell metabolic adaptations, decrease in ROS production, and cell cycle arrest in G1 accompanied by induction of apoptosis are late events occurring after 24h of MSA treatment in A549 cells. Our findings suggest that FOXO3a is a relevant mediator of the antiproliferative effects of MSA. This new evidence on the mechanistic action of MSA can open new avenues in exploiting its antitumour properties and in the optimal design of novel combination therapies. We present MSA as a promising chemotherapeutic agent with synergistic antiproliferative effects with cisplatin. (C) 2015 Elsevier Ltd. All rights reserved.
dc.description.sponsorshipMinisterio de Ciencia e Innovacion, Spain [SAF2011-25726]; Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR)-Generalitat de Catalunya [2014SGR1017]; Ministerio de Economia y Competitividad, Spain [SAF2014-56059-R]; National Institute of Health, USA [1R01CA118434-01A2, 1P01CA163223-01A1]; National Science Foundation, USA [EPS-0447479]; prize ICREA Academia for excellence in research; ICREA Foundation-Generalitat de Catalunya
dc.identifier.doihttps://doi.org/10.1016/j.phrs.2015.09.009
dc.identifier.issn1043-6618
dc.identifier.urihttp://hdl.handle.net/10400.1/11207
dc.language.isoeng
dc.peerreviewedyes
dc.publisherElsevier
dc.relationCentre for Biomedical Research
dc.subjectProstate-cancer cells
dc.subjectForkhead transcription factors
dc.subjectIsotope-resolved metabolomics
dc.subjectHuman lung-cancer
dc.subjectCarcinoma-cells
dc.subjectReactive oxygen
dc.subjectIn-vivo
dc.subjectSelenium-compounds
dc.subjectSignaling pathway
dc.subjectCycle regulation
dc.subjectFOXO
dc.subjectAkt
dc.titleMethylseleninic acid promotes antitumour effects via nuclear FOXO3a translocation through Akt inhibition
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCentre for Biomedical Research
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FBIM%2F04773%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F84634%2F2012/PT
oaire.citation.endPage234
oaire.citation.startPage218
oaire.citation.titlePharmacological Research
oaire.citation.volume102
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamSFRH
person.familyNameHill
person.familyNameLink
person.givenNameRichard
person.givenNameWolfgang
person.identifier803637
person.identifier.ciencia-id6910-952E-242A
person.identifier.orcid0000-0003-0394-6048
person.identifier.orcid0000-0002-3340-5165
person.identifier.scopus-author-id55266604200
person.identifier.scopus-author-id35368713800
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
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