MTOR Inhibition Leads to Src-Mediated EGFR Internalisation and Degradation in Glioma Cells

Barbara Colella,Mayra Colardo,Sabrina Di Bartolomeo,Marco Segatto,Claudia Contadini,Daniela Barilà,Guillermo Velasco,Cristina Saiz-Ladera,Gianna Iannone,Claudia Fuoco

doi:10.3390/cancers12082266

Abstract

Epidermal Growth Factor receptor (EGFR) is a tyrosine kinase receptor widely expressed on the surface of numerous cell types, which activates several downstream signalling pathways involved in cell proliferation, migration and survival. EGFR alterations, such as overexpression or mutations, have been frequently observed in several cancers, including glioblastoma (GBM), and are associated to uncontrolled cell proliferation. Here we show that the inhibition of mammalian target of Rapamycin (mTOR) mediates EGFR delivery to lysosomes for degradation in GBM cells, independently of autophagy activation. Coherently with EGFR internalisation and degradation, mTOR blockade negatively affects the mitogen activated protein/extracellular signal-regulated kinase (MAPK)/ERK pathway. Furthermore, we provide evidence that Src kinase activation is required for EGFR internaliation upon mTOR inhibition. Our results further support the hypothesis that mTOR targeting may represent an effective therapeutic strategy in GBM management, as its inhibition results in EGFR degradation and in proliferative signal alteration.

Highlights

Epidermal Growth Factor receptor (EGFR), known as ErbB1 or HER1, belongs to the tyrosine kinase receptors family (RTK) and regulates epithelial tissue development and homeostasis [1].In physiological conditions, inactive RTK receptors continuously travel through the endocytic compartment, by slow internalisation and recycling to the plasma membrane
We demonstrated that autophagy induction by nutrient starvation or by mammalian target of Rapamycin (mTOR) inhibition impairs migration and invasion in glioblastoma cells through reversing the Epithelial-to-Mesenchymal Transition (EMT) process and inhibiting the Wnt/β-catenin pathway [23,24,25]
We found that mTOR inhibition delocalises EGFR from the plasma membrane to the cytoplasm in Glioblastoma multiforme (GBM) cellular models

Summary

Introduction

Epidermal Growth Factor receptor (EGFR), known as ErbB1 or HER1, belongs to the tyrosine kinase receptors family (RTK) and regulates epithelial tissue development and homeostasis [1]. Inactive RTK receptors continuously travel through the endocytic compartment, by slow internalisation and recycling to the plasma membrane. EGFR activation and signal transduction inside the cell, regulating cell growth, differentiation, proliferation and migration [2,3]. Once internalised in early endosomes, EGFR can be recycled to the cell surface or delivered to lysosomes for degradation, in a delicate balance between continuous signalling from cell surface/endosomal compartments and signal attenuation from the degradative route [4,9].

Methods

Findings

Discussion

Conclusion