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C3G knock-down enhances migration and invasion by increasing Rap1-mediated p38α activation, while it impairs tumor growth through p38α-independent mechanisms

AuthorsPriego, Neibla; Arechederra, María; Sequera, Celia; Bragado, Paloma ; Vázquez-Carballo, Ana; Gutiérrez-Uzquiza, Álvaro; Martín-Granado, Víctor; Ventura, Juan José; Kazanietz, Marcelo G.; Guerrero Arroyo, María del Carmen ; Porras, Almudena
p38 MAPK
Issue Date2016
PublisherImpact Journals
CitationOncotarget 7(29): 45060-45078 (2016)
AbstractC3G, a Guanine nucleotide Exchange Factor (GEF) for Rap1 and R-Ras, has been shown to play important roles in development and cancer. Previous studies determined that C3G regulates cell death through down-regulation of p38α MAPK activity. Here, we found that C3G knock-down in MEFs and HCT116 cells promotes migration and invasion through Rap1-mediated p38α hyper-activation. These effects of C3G were inhibited by Rap1 knock-down or inactivation. The enhanced migration observed in C3G depleted HCT116 cells was associated with reduction in E-cadherin expression, internalization of ZO-1, actin cytoskeleton reorganization and decreased adhesion. We also found that matrix metalloproteases MMP2 and MMP9 are involved in the pro-invasive effect of C3G down-regulation. Additionally, our studies revealed that both C3G and p38α collaborate to promote growth of HCT116 cells in vitro and in vivo, possibly by enhancing cell survival. In fact, knocking-down C3G or p38α individually or together promoted cell death in vitro, although only the double C3G-p38α silencing was able to increase cell death within tumors. Notably, we found that the pro-tumorigenic function of C3G does not depend on p38α or Rap1 activation. Altogether, our studies uncover novel mechanisms by which C3G controls key aspects of tumorigenesis.
Publisher version (URL)https://doi.org/10.18632/oncotarget.9911
Identifiersdoi: 10.18632/oncotarget.9911
issn: 1949-2553
Appears in Collections:(IBMCC) Artículos
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