D-Propranolol Impairs EGFR Trafficking and Destabilizes Mutant p53 Counteracting AKT Signaling and Tumor Malignancy

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dc.contributor.authorBarra, Jonathan
dc.contributor.authorCerda-Infante, Javier
dc.contributor.authorSandoval, Lisette
dc.contributor.authorGajardo-Meneses, Patricia
dc.contributor.authorHenriquez, Jenny F.
dc.contributor.authorLabarca, Mariana
dc.contributor.authorMetz, Claudia
dc.contributor.authorVenegas, Jaime
dc.contributor.authorRetamal, Claudio
dc.contributor.authorOyanadel, Claudia
dc.contributor.authorCancino, Jorge
dc.contributor.authorSoza, Andrea
dc.contributor.authorCuello, Mauricio A.
dc.contributor.authorCarlos Roa, Juan
dc.contributor.authorMontecinos, Viviana P.
dc.contributor.authorGonzalez, Alfonso
dc.date.accessioned2025-01-20T22:13:55Z
dc.date.available2025-01-20T22:13:55Z
dc.date.issued2021
dc.description.abstractSimple 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.
dc.fuente.origenWOS
dc.identifier.doi10.3390/cancers13143622
dc.identifier.eissn2072-6694
dc.identifier.urihttps://doi.org/10.3390/cancers13143622
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/94463
dc.identifier.wosidWOS:000676307200001
dc.issue.numero14
dc.language.isoen
dc.revistaCancers
dc.rightsacceso restringido
dc.subjectEGFR
dc.subjectAKT
dc.subjectp53
dc.subjectHSP90
dc.subjectD-Propranolol
dc.subjectphosphatidic acid
dc.subjectPKA
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleD-Propranolol Impairs EGFR Trafficking and Destabilizes Mutant p53 Counteracting AKT Signaling and Tumor Malignancy
dc.typeartículo
dc.volumen13
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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