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dc.contributor.authorPrieto, Ignacio
dc.contributor.authorRubio Alarcón, Carmen
dc.contributor.authorGarcía-Gómez, Raquel
dc.contributor.authorBerdún Hernández, Rebeca
dc.contributor.authorUrgel, Tamara
dc.contributor.authorPortero Otín, Manuel
dc.contributor.authorPamplona Gras, Reinald
dc.contributor.authorMartínez-Ruiz, Antonio
dc.contributor.authorRuiz-Sanz, José Ignacio
dc.contributor.authorRuiz-Larrea, M. Begoña
dc.contributor.authorJové Font, Mariona
dc.contributor.authorCerdán, Sebastián
dc.contributor.authorMonsalve, María
dc.date.accessioned2020-11-03T12:20:35Z
dc.date.available2020-11-03T12:20:35Z
dc.date.issued2020-01-01
dc.identifier.issn2213-2317
dc.identifier.urihttp://hdl.handle.net/10459.1/69763
dc.description.abstractPGC-1α controls, to a large extent, the capacity of cells to respond to changing nutritional requirements and energetic demands. The key role of metabolic reprogramming in tumor development has highlighted the potential role of PGC-1α in cancer. To investigate how loss of PGC-1α activity in primary cells impacts the oncogenic characteristics of spontaneously immortalized cells, and the mechanisms involved, we used the classic 3T3 protocol to generate spontaneously immortalized mouse embryonic fibroblasts (iMEFs) from wild-type (WT) and PGC-1α knockout (KO) mice and analyzed their oncogenic potential in vivo and in vitro. We found that PGC-1α KO iMEFs formed larger and more proliferative primary tumors than WT counterparts, and fostered the formation of lung metastasis by B16 melanoma cells. These characteristics were associated with the reduced capacity of KO iMEFs to respond to cell contact inhibition, in addition to an increased ability to form colonies in soft agar, an enhanced migratory capacity, and a reduced growth factor dependence. The mechanistic basis of this phenotype is likely associated with the observed higher levels of nuclear β-catenin and c-myc in KO iMEFs. Evaluation of the metabolic adaptations of the immortalized cell lines identified a decrease in oxidative metabolism and an increase in glycolytic flux in KO iMEFs, which were also more dependent on glutamine for their survival. Furthermore, glucose oxidation and tricarboxylic acid cycle forward flux were reduced in KO iMEF, resulting in the induction of compensatory anaplerotic pathways. Indeed, analysis of amino acid and lipid patterns supported the efficient use of tricarboxylic acid cycle intermediates to synthesize lipids and proteins to support elevated cell growth rates. All these characteristics have been observed in aggressive tumors and support a tumor suppressor role for PGC-1α, restraining metabolic adaptations in cancer.
dc.description.sponsorshipThis work was funded by grants from the Spanish “Ministerio de Ciencia, Innovación y Universidades” (MICINN) and ERDF/FEDER funds, SAF2012-37693, SAF2015-63904-R, SAF2015-71521-REDC, RTI2018-093864-B-I00 to M.M., SAF2017-83043-R and B2017/BMD-3724 to S·C., PI15/00107 to A.M.R, the University of the Basque Country UPV/EHU grant GIU16/62) to J.l.R.S. and M.B.R.L., and the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 721236-TREATMENT to M.M.
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherElsevier
dc.relationMICINN/PN2008-2011/SAF2012-37693
dc.relationMINECO/PN2013-2016/SAF2015-63904-R
dc.relationMINECO/PN2013-2016/SAF2015-71521-REDC
dc.relationMINECO/PN2013-2016/RTI2018-093864-B-I00
dc.relationMINECO/PN2013-2016/SAF2017-83043-R
dc.relation.isformatofReproducció del document publicat a: https://doi.org/10.1016/j.redox.2019.101396
dc.relation.ispartofRedox Biology, 2020, vol. 29, p. 101396
dc.rightscc-by-nc-nd (c) Priero et al., 2020
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es
dc.subjectPGC-1α
dc.subjectMetabolism
dc.subjectCancer
dc.subjectTumor
dc.subjectMetastasis
dc.titleMetabolic adaptations in spontaneously immortalized PGC-1α knock-out mouse embryonic fibroblasts increase their oncogenic potential
dc.typeinfo:eu-repo/semantics/article
dc.date.updated2020-11-03T12:20:36Z
dc.identifier.idgrec030440
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.identifier.doihttps://doi.org/10.1016/j.redox.2019.101396
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/H2020/721236/EU/TREATMENT


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cc-by-nc-nd (c) Priero et al., 2020
Except where otherwise noted, this item's license is described as cc-by-nc-nd (c) Priero et al., 2020