Mechanobiology of Autophagy: The Unexplored Side of Cancer

Abstract

Proper execution of cellular function, maintenance of cellular homeostasis and cell survival depend on functional integration of cellular processes and correct orchestration of cellular responses to stresses. Cancer transformation is a common negative consequence of mismanagement of coordinated response by the cell. In this scenario, by maintaining the balance among synthesis, degradation, and recycling of cytosolic components including proteins, lipids, and organelles the process of autophagy plays a central role. Several environmental stresses activate autophagy, among those hypoxia, DNA damage, inflammation, and metabolic challenges such as starvation. In addition to these chemical challenges, there is a requirement for cells to cope with mechanical stresses stemming from their microenvironment. Cells accomplish this task by activating an intrinsic mechanical response mediated by cytoskeleton active processes and through mechanosensitive protein complexes which interface the cells with their mechano-environment. Despite autophagy and cell mechanics being known to play crucial transforming roles during oncogenesis and malignant progression their interplay is largely overlooked. In this review, we highlight the role of physical forces in autophagy regulation and their potential implications in both physiological as well as pathological conditions. By taking a mechanical perspective, we wish to stimulate novel questions to further the investigation of the mechanical requirements of autophagy and appreciate the extent to which mechanical signals affect this process.

Mechanical Properties in the Glioma Microenvironment: Emerging Insights and Theranostic Opportunities

“…In addition to directly inhibiting mechanical signal transduction, another feasible approach is to target the downstream molecular mechanisms and cellular processes that promote disease progression. One such target is autophagy which has been implicated in treatment resistance in various cancers including GBM (138)(139)(140). Recent studies have shown that the process of autophagy is altered by mechanical stimuli and signal transduction primarily through two mechanisms: 1) crosstalk between the shared regulatory proteins in autophagy and mechanical signal transduction pathway or 2) competition for molecular substrates utilized in both processes such as cytoskeletal elements (138).…”

“…One such target is autophagy which has been implicated in treatment resistance in various cancers including GBM (138)(139)(140). Recent studies have shown that the process of autophagy is altered by mechanical stimuli and signal transduction primarily through two mechanisms: 1) crosstalk between the shared regulatory proteins in autophagy and mechanical signal transduction pathway or 2) competition for molecular substrates utilized in both processes such as cytoskeletal elements (138). Several common pathways have been described in the literature and include the YAP/TAZ axis, JAK-mediated signal transduction, and the expression of EGFR (138,141,142).…”

“…Recent studies have shown that the process of autophagy is altered by mechanical stimuli and signal transduction primarily through two mechanisms: 1) crosstalk between the shared regulatory proteins in autophagy and mechanical signal transduction pathway or 2) competition for molecular substrates utilized in both processes such as cytoskeletal elements (138). Several common pathways have been described in the literature and include the YAP/TAZ axis, JAK-mediated signal transduction, and the expression of EGFR (138,141,142). Dupont et al demonstrate in a series of experiments that the transcriptional regulators YAP/TAZ are required for transducing mechanical cues from the microenvironment and specifically the elasticity of the ECM (96).…”

The Autophagic Route of E-Cadherin and Cell Adhesion Molecules in Cancer Progression

“…Epithelial cells are susceptible to several mechanical stimuli resulting from the cell-to-cell interactions and the extracellular matrix (e.g., composition, stiffness, and density), as well as fluid pressure and lateral stretch and compression required for the physiological function of several organs [ 168 ].…”

Enhanced Photothermal Therapy of Breast Cancer via Co-Loading With Autophagy Inhibitor

“…Such resistance mainly originates from an "autophagy" mechanism in the cell. [14,15] Autophagy represents an important cellular pathway that breaks down impaired organelles, aged proteins and other constituents, reusing them as cellular nutrients for self-renewal. [16,17] Additionally, autophagy has a vital function in resisting cell stress as well as various treatment methods.…”