English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/219318
Share/Impact:
Statistics
logo share SHARE   Add this article to your Mendeley library MendeleyBASE
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:

Title

Metabolic adaptations in spontaneously immortalized PGC-1a knock-out mouse embryonic fibroblasts increase their oncogenic potential

AuthorsMonsalve, María ; Prieto, Ignacio; Rubio, Carmen; García, Raquel; Berdún, Rebeca; Portero, Manuel; Pamplona, Reinald; Martínez-Ruiz, Antonio ; Ruiz-Sanz, José Ignacio; Ruiz-Larrea, M. Begoña; Jove, Mariona; Cerdán, Sebastián
Issue Date16-Jul-2019
CitationSEBBN 19 Madrid (2019)
AbstractPGC-1a 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-1a in cancer. To investigate how loss of PGC-1a 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-1a knockout (KO) mice and analyzed their oncogenic potential in vivo and in vitro. We found that PGC-1a 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 b-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, analysisi of aminoacid 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-1a, restraining metabolic adaptations in cancer.
DescriptionTrabajo presentado en la SEBBN 19 Madrid, celebrada en Madrid del 16 al 19 de julio de 2019.
URIhttp://hdl.handle.net/10261/219318
Appears in Collections:(IIBM) Comunicaciones congresos
Files in This Item:
File Description SizeFormat 
accesoRestringido.pdf15,38 kBAdobe PDFThumbnail
View/Open
Show full item record
Review this work
 


WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.