Browsing by Author "Balboa, Elisa"

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    c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder
    (Cell Press, 2020) Contreras, Pablo; Tapia, Pablo; González-Hodar, Lila; Peluso, Ivana; Soldati, Chiara; Napoiotano, Gennaro; Matarese, María; Las Heras, Macarena; Valls, Cristian; Martínez, Alexis; Balboa, Elisa; Castro, Juan; Nancy, Leal; Platt, Frances; Sobota, Andrzej; Winter, Dominic; Klein, Andrés; Medina, Diego; Ballabio, Andrea; Alvarez, Alejandra; Zanlungo, Silvana
    The transcription factor EB (TFEB) has emerged as a master regulator of lysosomal biogenesis, exocytosis, and autophagy, promoting the clearance of substrates stored in cells. c-Abl is a tyrosine kinase that participates in cellular signaling in physiological and pathophysiological conditions. In this study, we explored the connection between c-Abl and TFEB. Here, we show that under pharmacological and genetic c-Abl inhibition, TFEB translocates into the nucleus promoting the expression of its target genes independently of its well-known regulator, mammalian target of rapamycin complex 1. Active c-Abl induces TFEB phosphorylation on tyrosine and the inhibition of this kinase promotes lysosomal biogenesis, autophagy, and exocytosis. c-Abl inhibition in Niemann-Pick type C (NPC) models, a neurodegenerative disease characterized by cholesterol accumulation in lysosomes, promotes a cholesterol-lowering effect in a TFEB-dependent manner. Thus, c-Abl is a TFEB regulator that mediates its tyrosine phosphorylation, and the inhibition of c-Abl activates TFEB promoting cholesterol clearance in NPC models.
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    Pannexin-1 expression in tumor cells correlates with colon cancer progression and survival
    (2024) Fierro, Aaron; Landskron, Glauben; Camhi, Ilan; Basterrechea, Benjamín; Parada, Daniela; Lobos-González, Lorena; Dubois, Karen; Araneda, Catalina; Romero, Camila; Domínguez, Antonia; Vásquez, Gonzalo; López, Francisco; Alvarez, Karin; González, Carlos; Hager, Carolina; Balboa, Elisa; Eugenin, Eliseo; Hermoso, Marcela; De la Fuente, Marjorie
    Aims: Pannexin-1 (PANX1) is a hemichannel that releases ATP upon opening, initiating inflammation, cell proliferation, and migration. However, the role of PANX1 channels in colon cancer remains poorly understood, thus constituting the focus of this study. Main methods: PANX1 mRNA expression was analyzed using multiple cancer databases. PANX1 protein expression and distribution were evaluated by immunohistochemistry on primary tumor tissue and non-tumor colonic mucosa from colon cancer patients. PANX1 inhibitors (probenecid or 10Panx) were used to assess colon cancer cell lines viability. To study the role of PANX1 in vivo, a subcutaneous xenograft model using HCT116 cells was performed in BALB/c NOD/SCID immunodeficient mice to evaluate tumor growth under PANX1 inhibition using probenecid. Key findings: PANX1 mRNA was upregulated in colon cancer tissue compared to non-tumor colonic mucosa. Elevated PANX1 mRNA expression in tumors correlated with worse disease-free survival. PANX1 protein abundance was increased on tumor cells compared to epithelial cells in paired samples, in a cancer stage-dependent manner. In vitro and in vivo experiments indicated that blocking PANX1 reduced cell viability and tumor growth. Significance: PANX1 can be used as a biomarker of colon cancer progression and blocking PANX1 channel opening could be used as a potential therapeutic strategy against this disease.
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    Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage
    (2021) Balboa, Elisa; Marín, Tamara; Oyarzún, Juan Esteban; Contreras, Pablo S.; Hardt, Robert; Bosch, Thea van den; Alvarez, Alejandra R.; Rebolledo-Jaramillo, Boris; Klein, Andrés; Winter, Dominic; Zanlungo, Silvana
    Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1−/− mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD

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