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Article

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

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Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago 7510157, Chile
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Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile
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Fundación Ciencia y Vida, Santiago 7780272, Chile
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Departamento de Hematología-Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330023, Chile
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Departamento de Ginecología-Obstetricia, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330023, Chile
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Departamento de Patología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330023, Chile
*
Author to whom correspondence should be addressed.
Current address: Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY 12208, USA.
Academic Editor: Donat Kögel
Cancers 2021, 13(14), 3622; https://doi.org/10.3390/cancers13143622
Received: 28 May 2021 / Revised: 28 June 2021 / Accepted: 13 July 2021 / Published: 20 July 2021
(This article belongs to the Section Molecular Cancer Biology)
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-α. 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. View Full-Text
Keywords: EGFR; AKT; p53; HSP90; D-Propranolol; phosphatidic acid; PKA EGFR; AKT; p53; HSP90; D-Propranolol; phosphatidic acid; PKA
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MDPI and ACS Style

Barra, J.; Cerda-Infante, J.; Sandoval, L.; Gajardo-Meneses, P.; Henriquez, J.F.; Labarca, M.; Metz, C.; Venegas, J.; Retamal, C.; Oyanadel, C.; Cancino, J.; Soza, A.; Cuello, M.A.; Roa, J.C.; Montecinos, V.P.; Gonzalez, A. D-Propranolol Impairs EGFR Trafficking and Destabilizes Mutant p53 Counteracting AKT Signaling and Tumor Malignancy. Cancers 2021, 13, 3622. https://doi.org/10.3390/cancers13143622

AMA Style

Barra J, Cerda-Infante J, Sandoval L, Gajardo-Meneses P, Henriquez JF, Labarca M, Metz C, Venegas J, Retamal C, Oyanadel C, Cancino J, Soza A, Cuello MA, Roa JC, Montecinos VP, Gonzalez A. D-Propranolol Impairs EGFR Trafficking and Destabilizes Mutant p53 Counteracting AKT Signaling and Tumor Malignancy. Cancers. 2021; 13(14):3622. https://doi.org/10.3390/cancers13143622

Chicago/Turabian Style

Barra, Jonathan, Javier Cerda-Infante, Lisette Sandoval, Patricia Gajardo-Meneses, Jenny F. Henriquez, Mariana Labarca, Claudia Metz, Jaime Venegas, Claudio Retamal, Claudia Oyanadel, Jorge Cancino, Andrea Soza, Mauricio A. Cuello, Juan C. Roa, Viviana P. Montecinos, and Alfonso Gonzalez. 2021. "D-Propranolol Impairs EGFR Trafficking and Destabilizes Mutant p53 Counteracting AKT Signaling and Tumor Malignancy" Cancers 13, no. 14: 3622. https://doi.org/10.3390/cancers13143622

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