MTOR Signaling Components in Tumor Mechanobiology.

Antonios N Gargalionis,Efthimia K Basdra,Kostas A Papavassiliou,Athanasios G Papavassiliou

doi:10.3390/ijms23031825

Abstract

Mechanistic target of rapamycin (mTOR) is a central signaling hub that integrates networks of nutrient availability, cellular metabolism, and autophagy in eukaryotic cells. mTOR kinase, along with its upstream regulators and downstream substrates, is upregulated in most human malignancies. At the same time, mechanical forces from the tumor microenvironment and mechanotransduction promote cancer cells’ proliferation, motility, and invasion. mTOR signaling pathway has been recently found on the crossroads of mechanoresponsive-induced signaling cascades to regulate cell growth, invasion, and metastasis in cancer cells. In this review, we examine the emerging association of mTOR signaling components with certain protein tools of tumor mechanobiology. Thereby, we highlight novel mechanisms of mechanotransduction, which regulate tumor progression and invasion, as well as mechanisms related to the therapeutic efficacy of antitumor drugs.

Highlights

Mechanistic target of rapamycin protein kinase was firstly identified as the pharmaceutical target of rapamycin, a macrolide that was isolated from the bacterium Streptomyces hygroscopicus and demonstrated immunosuppressive, neuroprotective, and anticancer properties [1,2,3]
Tumor mechanobiology is a distinct field that investigates the impact of aberrant mechanical forces on tumor development, progression, and therapy
Cancer cells communicate with their microenvironment and translate physical alterations, changes of extracellular matrix (ECM) rigidity, concentration of ligands, and reprogramming of cellular architecture into corresponding cellular response through mechanotransduction [5,6,7,21]

Summary

Introduction

Mechanistic target of rapamycin (mTOR) protein kinase was firstly identified as the pharmaceutical target of rapamycin, a macrolide that was isolated from the bacterium Streptomyces hygroscopicus and demonstrated immunosuppressive, neuroprotective, and anticancer properties [1,2,3]. MTOR is a dominant regulator of cell growth, both in cell size and number, by transmitting signals inside the cell regarding the abundance of cellular nutrients and energy sources. In this way, mTOR directs biosynthesis or deconstruction of macromolecules and supports metabolic processes of cell growth and proliferation [4]. We examine mTOR, upstream regulators, and downstream substrates in conjunction with documented cellular tools of mechanobiology. In this context, we aim to highlight the crosstalk of signal transduction mechanisms and provide insights for the better therapeutic efficacy of anticancer strategies

Tumor Mechanobiology

ECM Stiffness-Induced Mechanisms

Mechanosensitive Membrane Protein Complexes and Ligands

Mechanosensitive Ion Channels and Cytoskeletal Components

Crosstalk between the MTOR and Hippo Pathway

Conclusions