The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion

Abstract

Autophagy is a cellular degradation process integral for promoting cellular adaptation during metabolic stress while also functioning as a cellular homeostatic mechanism. Mounting evidence also demonstrates that autophagy is induced upon loss of integrin-mediated cell attachments to the surrounding extracellular matrix (ECM). Analogous to its established cytoprotective role during nutrient starvation, autophagy protects cells from detachment-induced cell death, termed anoikis. Here, we review the significance of autophagy as an anoikis resistance pathway, focusing on the intracellular signals associated with integrins that modulate the autophagy response and dictate the balance between cell death and survival following loss of cell-matrix contact. In addition, we highlight recent studies demonstrating that autophagy functions in the upstream regulation of integrin-mediated cell adhesion via the control of focal adhesion remodeling, and discuss how these emerging interconnections between integrin-mediated adhesion pathways and autophagy influence cancer progression and metastasis.

The transformics assay: first steps for the development of an integrated approach to investigate the malignant cell transformation in vitro

“…Furthermore, the highest concentration was able to significantly perturb the pathway that referred to the cytoskeleton remodeling, the ‘Cytoskeleton remodeling_RalA regulation pathway,’ while the involvement of cell adhesion mechanisms (‘Cell adhesion_ECM remodeling’) appears to be related mainly to the lowest concentration (0.04 µg/ml). The loss of cell attachment to the extracellular matrix is related to the early cell response to stress, as a cellular homeostatic mechanism that prevents cells from detachment-induced cell death (anoikis) ( 20 ). This provides key evidence of the likely pivotal event sustaining the adaptive response in cells treated with the lowest concentration.…”

Metastatic cells are preferentially vulnerable to lysosomal inhibition

“…Invasive and metastatic cells have particularly large numbers of lysosomes located at the periphery of the cell instead of in their typical juxtanuclear region. These peripheral lysosomes have recently been implicated in the regulation and degradation of focal adhesion proteins, the degradation of Rho proteins, including RhoA, and the degradation of extracellular matrix upon exocytosis; these processes regulate cellular migration and invasion of metastatic cells (37,38). It may be that these processes are involved in the connection between metastasis and additional sensitivity to lysosomal inhibitors.…”

A novel non-sulphamoylated 2-methoxyestradiol derivative causes detachment of breast cancer cells by rapid disassembly of focal adhesions

“…However, further investigation into apoptotic cascades such as the various caspases, Bid, Bax and Bcl-2 activation could be performed. Increased autophagy has also been linked to anoikis resistance in cancer cells [ 21 ]. Future studies will focus on this phenomenon related to the induced loss of cell adhesion by EE-15-one.…”