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

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.

DMT1 bridges endosomes and mitochondria to modulate mitochondrial iron translocation

“…Invasive migration capacity was measured using an inverted invasion assay, as previously described (Barra et al, 2021; Hennigan et al, 1994). Briefly, Matrigel (Corning) 5 mg/mL, mixed with fibronectin (25 μg/mL), was polymerized within 12-well Transwell™ polycarbonate filter inserts (8-μm pore size; Corning) for 1 h at 37°C.…”

Circulating Mesenchymal Stromal Cells in Patients with Infantile Hemangioma: Evaluation of Their Functional Capacity and Gene Expression Profile

“…However, very recently, it has been reported both an inflammatory environment in IH with multiple lesions [40] and a role of inflammation in defining the paracrine profile of MSCs, possibly altering the expression of angiogenic cytokines such as TGFα, in favor of a major reparative capacity [41]. In addition, propranolol and its isomers have been described in in vitro studies to promote the internalization of the MSC membrane receptors binding either EGF or TGFα; a similar mechanism may alter in vivo the TGFα gene expression [42]. Of note, cMSCs of patients at the end of therapy with propranolol showed an expression profile not different from that of cMSCs from CTRLs.…”

Recent Advances on Mutant p53: Unveiling Novel Oncogenic Roles, Degradation Pathways, and Therapeutic Interventions

“…Furthermore, C-terminal phosphorylation of Hsp70 as well of Hsp90, by CK1, CK2 and GSK3-β, favor the binding to HOP while preventing that to CHIP, facilitating the protein folding over protein ubiquitin-mediated degradation, two opposite functions that these HSPs may play [ 148 ]. Also, the phosphorylation of HSP90 by PKA may positively influence its interaction with mutp53 [ 149 ] ( Figure 8 ). Considering that HSP70 and HSP90 can be phosphorylated at different residues, the impact of this PTM on their function remains still incomplete and the same also applies to the kinases and phosphatases that regulate HSP phosphorylation.…”