Abstract
Cancer therapy may be improved by the simultaneous interference of two or more onco-genic 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 in-hibitors 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 degrada-tion. 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.
| Original language | English |
|---|---|
| Article number | 3622 |
| Journal | Cancers |
| Volume | 13 |
| Issue number | 14 |
| DOIs | |
| State | Published - 2021 |
Bibliographical note
Funding Information:Funding: This work received financial support from the Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) “Programa de Apoyo a Centros con Financiamiento Basal” AFB170005 to the Center for Aging and Regeneration (CARE) (A.G. and J.B.) and AFB170004 to Fun-dación Ciencia & Vida (A.G.); Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) grants #1181907 (A.G.), #1201083 (M.A.C.), # 11181015 (C.O.), #1150397 (V.P.M.); Doctoral fellowship CONICYT #21140735 (J.B.). The authors acknowledge the services provided by UC CINBIOT Animal Facility funded by PIA CONICYT Program for Associative Research, of the Chilean National Council for Science and Technology ECM-07.
Funding Information:
This work received financial support from the Comisi?n Nacional de Investigaci?n Cient?fica y Tecnol?gica (CONICYT) ?Programa de Apoyo a Centros con Financiamiento Basal? AFB170005 to the Center for Aging and Regeneration (CARE) (A.G. and J.B.) and AFB170004 to Fun-daci?n Ciencia & Vida (A.G.); Fondo Nacional de Desarrollo Cient?fico y Tecnol?gico (FONDECYT) grants #1181907 (A.G.), #1201083 (M.A.C.), # 11181015 (C.O.), #1150397 (V.P.M.); Doctoral fellowship CONICYT #21140735 (J.B.). The authors acknowledge the services provided by UC CINBIOT Animal Facility funded by PIA CONICYT Program for Associative Research, of the Chilean National Council for Science and Technology ECM-07. Acknowledgments: The authors thank Karen Vousden (Francis Crick Intitute, UK) for providing EIH1299 cells and Jin Zhang (University of California San Diego) for the plasmid encoding the PKA-activity biosensor.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
ASJC Scopus subject areas
- Oncology
- Cancer Research
