Cancers, Vol. 13, Pages 3622: D-Propranolol Impairs EGFR Trafficking and Destabilizes Mutant p53 Counteracting AKT Signaling and Tumor Malignancy

Cancers, Vol. 13, Pages 3622: D-Propranolol Impairs EGFR Trafficking and Destabilizes Mutant p53 Counteracting AKT Signaling and Tumor Malignancy Cancers doi: 10.3390/cancers13143622 Authors: Jonathan Barra 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 Carlos Roa Viviana P. Montecinos Alfonso Gonzalez 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 inter...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research