Person: Bragado Domingo, Paloma
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First Name
Paloma
Last Name
Bragado Domingo
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Bioquímica y Biología Molecular
Area
Bioquímica y Biología Molecular
Identifiers
4 results
Search Results
Now showing 1 - 4 of 4
Item C3G Protein, a New Player in Glioblastoma(International Journal of Molecular Sciences, 2021) Manzano, Sara; Gutierrez Uzquiza, Álvaro; Bragado Domingo, Paloma; Cuesta Martínez, Ángel; Guerrero, Carmen; Porras Gallo, AlmudenaC3G (RAPGEF1) is a guanine nucleotide exchange factor (GEF) for GTPases from the Ras superfamily, mainly Rap1, although it also acts through GEF-independent mechanisms. C3G regulates several cellular functions. It is expressed at relatively high levels in specific brain areas, playing important roles during embryonic development. Recent studies have uncovered different roles for C3G in cancer that are likely to depend on cell context, tumour type, and stage. However, its role in brain tumours remained unknown until very recently. We found that C3G expression is downregulated in GBM, which promotes the acquisition of a more mesenchymal phenotype, enhancing migration and invasion, but not proliferation. ERKs hyperactivation, likely induced by FGFR1, is responsible for this pro-invasive effect detected in C3G silenced cells. Other RTKs (Receptor Tyrosine Kinases) are also dysregulated and could also contribute to C3G effects. However, it remains undetermined whether Rap1 is a mediator of C3G actions in GBM. Various Rap1 isoforms can promote proliferation and invasion in GBM cells, while C3G inhibits migration/invasion. Therefore, other RapGEFs could play a major role regulating Rap1 activity in these tumours. Based on the information available, C3G could represent a new biomarker for GBM diagnosis, prognosis, and personalised treatment of patients in combination with other GBM molecular markers. The quantification of C3G levels in circulating tumour cells (CTCs) in the cerebrospinal liquid and/or circulating fluids might be a useful tool to improve GBM patient treatment and survival.Item The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase(Clinical Cancer Research, 2016) Bragado Domingo, Paloma; Lorente Pérez, María Del Mar; Salazar Roa, María; Velasco Díez, Guillermo; Tatiana Erazo; Anna Lopez-Plana; Pau Munoz-Guardiola; Patricia Fernandez-Nogueira; Jose A. García-Martínez; Gemma Fuster; Jordi Espadaler; Javier Hernandez-Losa; Jose Ramon Bayascas; Marc Cortal; Laura Vidal; Pedro Gascon; Mariana Gomez-Ferreria; Jose Alfon; Carles Domenech; Jose M. Lizcano; Jose M. LizcanoPurpose: ABTL0812 is a novel first-in-class, small molecule which showed antiproliferative effect on tumor cells in phenotypic assays. Here we describe the mechanism of action of this antitumor drug, which is currently in clinical development. Experimental Design: We investigated the effect of ABTL0812 on cancer cell death, proliferation, and modulation of intracellular signaling pathways, using human lung (A549) and pancreatic (MiaPaCa-2) cancer cells and tumor xenografts. To identify cellular targets, we performed in silico high-throughput screening comparing ABTL0812 chemical structure against ChEMBL15 database. Results: ABTL0812 inhibited Akt/mTORC1 axis, resulting in impaired cancer cell proliferation and autophagy-mediated cell death. In silico screening led us to identify PPARs, PPARα and PPARγ as the cellular targets of ABTL0812. We showed that ABTL0812 activates both PPAR receptors, resulting in upregulation of Tribbles-3 pseudokinase (TRIB3) gene expression. Upregulated TRIB3 binds cellular Akt, preventing its activation by upstream kinases, resulting in Akt inhibition and suppression of the Akt/mTORC1 axis. Pharmacologic inhibition of PPARα/γ or TRIB3 silencing prevented ABTL0812-induced cell death. ABTL0812 treatment induced Akt inhibition in cancer cells, tumor xenografts, and peripheral blood mononuclear cells from patients enrolled in phase I/Ib first-in-human clinical trial. Conclusions: ABTL0812 has a unique and novel mechanism of action, that defines a new and drugable cellular route that links PPARs to Akt/mTORC1 axis, where TRIB3 pseudokinase plays a central role. Activation of this route (PPARα/γ-TRIB3-Akt-mTORC1) leads to autophagy-mediated cancer cell death. Given the low toxicity and high tolerability of ABTL0812, our results support further development of ABTL0812 as a promising anticancer therapy.Item Met signaling in cardiomyocytes is required for normal cardiac function in adult mice(Biochimica et Biophysica Acta (Molecular Basis of disease), 2013) Arechederra Calderón, María; Carmona Mejías, Rita; González-Nuñez, María; Gutiérrez Uzquiza, Álvaro; Bragado Domingo, Paloma; Cruz-González, Ignacio; Cano Rincón, Elena; Guerrero Arroyo, María Del Carmen; Sánchez Muñoz, Aranzazu; López-Novoa, José Miguel; Schneider, Michael D.; Maina, Flavio; Muñoz-Chápuli, Ramón; Porras Gallo, María AlmudenaHepatocyte growth factor (HGF) and its receptor, Met, are key determinants of distinct developmental processes. Although HGF exerts cardio-protective effects in a number of cardiac pathologies, it remains unknown whether HGF/Met signaling is essential for myocardial development and/or physiological function in adulthood. We therefore investigated the requirement of HGF/Met signaling in cardiomyocyte for embryonic and postnatal heart development and function by conditional inactivation of the Met receptor in cardiomyocytes using the Cre-α-MHC mouse line (referred to as α-MHCMet-KO). Although α-MHCMet-KO mice showed normal heart development and were viable and fertile, by 6 months of age, males developed cardiomyocyte hypertrophy, associated with interstitial fibrosis. A significant upregulation in markers of myocardial damage, such as β-MHC and ANF, was also observed. By the age of 9 months, α-MHCMet-KO males displayed systolic cardiac dysfunction. Mechanistically, we provide evidence of a severe imbalance in the antioxidant defenses in α-MHCMet-KO hearts involving a reduced expression and activity of catalase and superoxide dismutase, with consequent reactive oxygen species accumulation. Similar anomalies were observed in females, although with a slower kinetics. We also found that Met signaling down-regulation leads to an increase in TGF-β production and a decrease in p38MAPK activation, which may contribute to phenotypic alterations displayed in α-MHCMet-KO mice. Consistently, we show that HGF acts through p38α to upregulate antioxidant enzymes in cardiomyocytes. Our results highlight that HGF/Met signaling in cardiomyocytes plays a physiological cardio-protective role in adult mice by acting as an endogenous regulator of heart function through oxidative stress control.Item Inhibition of RAC1 activity in cancer associated fibroblasts favours breast tumour development through IL-1β upregulation(Cancer Letters, 2021) Martínez López, Angélica; García Casas, Ana; Bragado Domingo, Paloma; Orimo, Akira; Castañeda-Saucedo, Eduardo; Castillo Lluva, SoniaCancer-associated fibroblasts (CAFs) are highly abundant stromal components in the tumour microenvironment. These cells contribute to tumorigenesis and indeed, they have been proposed as a target for anti-cancer therapies. Similarly, targeting the Rho-GTPase RAC1 has also been suggested as a potential therapeutic target in cancer. Here, we show that targeting RAC1 activity, either pharmacologically or by genetic silencing, increases the pro-tumorigenic activity of CAFs by upregulating IL-1β secretion. Moreover, inhibiting RAC1 activity shifts the CAF subtype to a more aggressive phenotype. Thus, as RAC1 suppresses the secretion of IL-1β by CAFs, reducing RAC1 activity in combination with the depletion of this cytokine should be considered as an interesting therapeutic option for breast cancer in which tumour cells retain intact IL-1β signalling..