Browsing by Author "Labarca, Mariana"

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    D-Propranolol Impairs EGFR Trafficking and Destabilizes Mutant p53 Counteracting AKT Signaling and Tumor Malignancy
    (2021) Barra, Jonathan; Cerda-Infante, Javier; Sandoval, Lisette; Gajardo-Meneses, Patricia; Henriquez, Jenny F.; Labarca, Mariana; Metz, Claudia; Venegas, Jaime; Retamal, Claudio; Oyanadel, Claudia; Cancino, Jorge; Soza, Andrea; Cuello, Mauricio A.; Carlos Roa, Juan; Montecinos, Viviana P.; Gonzalez, Alfonso
    Simple Summary Cancer progression is frequently driven by altered functions of EGFR belonging to the tyrosine-kinase family of growth factor receptors and by the transcription factor p53, which is called the "genome guardian". We report that D-Propranolol, previously used for other purposes in human patients, has antitumor effects involving a redistribution of cell surface EGFR to intracellular compartments and degradation of gain-of-function mutants of p53 (GOF-mutp53). These effects can be seen in cancer cell lines expressing EGFR and GOF-mutp53 and are reproduced in vivo, reducing tumor growth and prolonging survival of xenografted mice. D-Propranolol is proposed as a prototype drug for a new strategy against highly aggressive EGFR- and mutp53-expressing tumors. Cancer therapy may be improved by the simultaneous interference of two or more oncogenic pathways contributing to tumor progression and aggressiveness, such as EGFR and p53. Tumor cells expressing gain-of-function (GOF) mutants of p53 (mutp53) are usually resistant to EGFR inhibitors and display invasive migration and AKT-mediated survival associated with enhanced EGFR recycling. D-Propranolol (D-Prop), the non-beta blocker enantiomer of propranolol, was previously shown to induce EGFR internalization through a PKA inhibitory pathway that blocks the recycling of the receptor. Here, we first show that D-Prop decreases the levels of EGFR at the surface of GOF mutp53 cells, relocating the receptor towards recycling endosomes, both in the absence of ligand and during stimulation with high concentrations of EGF or TGF-alpha. D-Prop also inactivates AKT signaling and reduces the invasive migration and viability of these mutp53 cells. Unexpectedly, mutp53 protein, which is stabilized by interaction with the chaperone HSP90 and mediates cell oncogenic addiction, becomes destabilized after D-Prop treatment. HSP90 phosphorylation by PKA and its interaction with mutp53 are decreased by D-Prop, releasing mutp53 towards proteasomal degradation. Furthermore, a single daily dose of D-Prop reproduces most of these effects in xenografts of aggressive gallbladder cancerous G-415 cells expressing GOF R282W mutp53, resulting in reduced tumor growth and extended mice survival. D-Prop then emerges as an old drug endowed with a novel therapeutic potential against EGFR- and mutp53-driven tumor traits that are common to a large variety of cancers.
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    Fragmentos de mundo: objetos y artefactos americanos en tránsito (siglos XVI-XX)
    (CHAM – Centro de Humanidades Faculdade de Ciências Sociais e Humanas da Universidade NOVA de Lisboa, 2023) Gaune Corradi, Rafael; Romano, Antonella; Goldman, Oury; Carrió Cataldi, Leonardo Ariel; Gänger, Stefanie; Labarca, Mariana; Sanfuentes, Olaya; Serra, Daniela; Urbina, Ximena; Kirsi Silva, Barbara
    Este volumen multilingüe invita a la reflexión en torno a la idea de “fragmentación” y su papel en la producción de conocimiento. Destaca la dimensión fragmentaria de la transmisión y circulación de objetos y artefactos que convergieron y se trasladaron de América a Europa entre los siglos XVI y XX.
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    Galectin-8 counteracts folic acid-induced acute kidney injury and prevents its transition to fibrosis
    (2024) Perez-Moreno, Elisa; Toledo, Tomas; Campusano, Pascale; Zuniga, Sebastian; Azocar, Lorena; Feuerhake, Teo; Mendez, Gonzalo P.; Labarca, Mariana; Perez-Molina, Francisca; de la Pena, Adely; Herrera-Cid, Cristian; Ehrenfeld, Pamela; Godoy, Alejandro S.; Gonzalez, Alfonso; Soza, Andrea
    Acute kidney injury (AKI), characterized by a sudden decline in kidney function involving tubular damage and epithelial cell death, can lead to progressive tissue fibrosis and chronic kidney disease due to interstitial fibroblast activation and tissue repair failures that lack direct treatments. After an AKI episode, surviving renal tubular cells undergo cycles of dedifferentiation, proliferation and redifferentiation while fibroblast activity increases and then declines to avoid an exaggerated extracellular matrix deposition. Appropriate tissue recovery versus pathogenic fibrotic progression depends on fine-tuning all these processes. Identifying endogenous factors able to affect any of them may offer new therapeutic opportunities to improve AKI outcomes. Galectin-8 (Gal-8) is an endogenous carbohydrate-binding protein that is secreted through an unconventional mechanism, binds to glycosylated proteins at the cell surface and modifies various cellular activities, including cell proliferation and survival against stress conditions. Here, using a mouse model of AKI induced by folic acid, we show that pretreatment with Gal-8 protects against cell death, promotes epithelial cell redifferentiation and improves renal function. In addition, Gal-8 decreases fibroblast activation, resulting in less expression of fibrotic genes. Gal-8 added after AKI induction is also effective in maintaining renal function against damage, improving epithelial cell survival. The ability to protect kidneys from injury during both pre- and post-treatments, coupled with its anti-fibrotic effect, highlights Gal-8 as an endogenous factor to be considered in therapeutic strategies aimed at improving renal function and mitigating chronic pathogenic progression.
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    Galectin-8 Favors the Presentation of Surface-Tethered Antigens by Stabilizing the B Cell Immune Synapse
    (2018) Obino, Dorian; Fetler, Luc; Soza Gajardo, Andrea; Malbec, Odile; Saez, Jose; Labarca, Mariana; Oyanadel, Claudia; Del Valle Batalla, Felipe; Goles, Nicolas; Chikina, Aleksandra; Lankar, Danielle; Yuseff Sepúlveda, María Isabel; Segovia Miranda, Fabián Josué; Garcia, Camille; Léger, Thibaut; Gonzalez, Alfonso; Espéli, Marion; Lennon-Duménil, Ana-Maria
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    Sonic hedgehog is basolaterally sorted from the TGN and transcytosed to the apical domain involving Dispatched-1 at Rab11-ARE
    (2022) Sandoval, Lisette; Labarca, Mariana; Retamal, Claudio; Sanchez, Paula; Larrain, Juan; Gonzalez, Alfonso
    Hedgehog proteins (Hhs) secretion from apical and/or basolateral domains occurs in different epithelial cells impacting development and tissue homeostasis. Palmitoylation and cholesteroylation attach Hhs to membranes, and Dispatched-1 (Disp-1) promotes their release. How these lipidated proteins are handled by the complex secretory and endocytic pathways of polarized epithelial cells remains unknown. We show that polarized Madin-Darby canine kidney cells address newly synthesized sonic hedgehog (Shh) from the TGN to the basolateral cell surface and then to the apical domain through a transcytosis pathway that includes Rab11-apical recycling endosomes (Rab11-ARE). Both palmitoylation and cholesteroylation contribute to this sorting behavior, otherwise Shh lacking these lipid modifications is secreted unpolarized. Disp-1 mediates first basolateral secretion from the TGN and then transcytosis from Rab11-ARE. At the steady state, Shh predominates apically and can be basolaterally transcytosed. This Shh trafficking provides several steps for regulation and variation in different epithelia, subordinating the apical to the basolateral secretion.