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

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          Abstract

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          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.

          Abstract

          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.

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          A guided tour into subcellular colocalization analysis in light microscopy.

          It is generally accepted that the functional compartmentalization of eukaryotic cells is reflected by the differential occurrence of proteins in their compartments. The location and physiological function of a protein are closely related; local information of a protein is thus crucial to understanding its role in biological processes. The visualization of proteins residing on intracellular structures by fluorescence microscopy has become a routine approach in cell biology and is increasingly used to assess their colocalization with well-characterized markers. However, image-analysis methods for colocalization studies are a field of contention and enigma. We have therefore undertaken to review the most currently used colocalization analysis methods, introducing the basic optical concepts important for image acquisition and subsequent analysis. We provide a summary of practical tips for image acquisition and treatment that should precede proper colocalization analysis. Furthermore, we discuss the application and feasibility of colocalization tools for various biological colocalization situations and discuss their respective strengths and weaknesses. We have created a novel toolbox for subcellular colocalization analysis under ImageJ, named JACoP, that integrates current global statistic methods and a novel object-based approach.
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            Mutant p53 in Cancer: New Functions and Therapeutic Opportunities

            Many different types of cancer show a high incidence of TP53 mutations, leading to the expression of mutant p53 proteins. There is growing evidence that these mutant p53s have both lost wild-type p53 tumor suppressor activity and gained functions that help to contribute to malignant progression. Understanding the functions of mutant p53 will help in the development of new therapeutic approaches that may be useful in a broad range of cancer types.
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              Putting p53 in Context.

              TP53 is the most frequently mutated gene in human cancer. Functionally, p53 is activated by a host of stress stimuli and, in turn, governs an exquisitely complex anti-proliferative transcriptional program that touches upon a bewildering array of biological responses. Despite the many unveiled facets of the p53 network, a clear appreciation of how and in what contexts p53 exerts its diverse effects remains unclear. How can we interpret p53's disparate activities and the consequences of its dysfunction to understand how cell type, mutation profile, and epigenetic cell state dictate outcomes, and how might we restore its tumor-suppressive activities in cancer?
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                20 July 2021
                July 2021
                : 13
                : 14
                : 3622
                Affiliations
                [1 ]Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago 7510157, Chile; barracj@ 123456amc.edu (J.B.); lpsandov@ 123456uc.cl (L.S.); mlabarcal@ 123456docente.uss.cl (M.L.); claudia.metz@ 123456uss.cl (C.M.); jvenegasc1@ 123456correo.uss.cl (J.V.); claudio.retamal@ 123456uss.cl (C.R.); claudia.oyanadel@ 123456uss.cl (C.O.); jorge.cancino@ 123456uss.cl (J.C.); andrea.soza@ 123456uss.cl (A.S.)
                [2 ]Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile
                [3 ]Fundación Ciencia y Vida, Santiago 7780272, Chile; pngajard@ 123456uc.cl
                [4 ]Departamento de Hematología-Oncología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330023, Chile; jocerda@ 123456uc.cl (J.C.-I.); jfhenriq@ 123456uc.cl (J.F.H.); vmontecinos@ 123456med.puc.cl (V.P.M.)
                [5 ]Departamento de Ginecología-Obstetricia, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330023, Chile; macuello@ 123456med.puc.cl
                [6 ]Departamento de Patología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330023, Chile; jcroa@ 123456med.puc.cl
                Author notes
                [* ]Correspondence: alfonso.gonzalez@ 123456uss.cl ; Tel.: +56-2-22606300
                [†]

                Current address: Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY 12208, USA.

                Author information
                https://orcid.org/0000-0002-8583-5079
                https://orcid.org/0000-0003-2812-0015
                https://orcid.org/0000-0001-8313-8774
                Article
                cancers-13-03622
                10.3390/cancers13143622
                8305715
                34298835
                d3a06b2f-be30-47fc-9c2e-bc9928b75896
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 28 May 2021
                : 13 July 2021
                Categories
                Article

                egfr,akt,p53,hsp90,d-propranolol,phosphatidic acid,pka
                egfr, akt, p53, hsp90, d-propranolol, phosphatidic acid, pka

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