Abstract
Cell adhesion is important in cancer metastasis. Malignant cells in cancer patients may be exposed to physical forces such as extracellular pressure and shear, that stimulate their adhesion to matrix proteins, endothelium and surgical wounds. Pressure induces phosphorylation of AKT and focal adhesion kinase (FAK), which are required for pressure-stimulated cancer cell adhesion, but what mediates this effect is unknown. ILK may influence cell adhesion and FAK and AKT phosphorylation in other settings. We therefore hypothesized that ILK might also regulate pressure-stimulated cancer cell adhesion through AKT and FAK phosphorylation. Silencing ILK by siRNA reduced basal cancer cell adhesion and prevented the stimulation of adhesion by pressure. ILK mediated pressure-stimulated adhesion through specifically regulating phosphorylation of AKT at Ser473 and FAK at Tyr397 and 576 as well as ILK association with FAK and AKT. The siRNA-mediated loss of function of ILK in regulating increase in adhesion by pressure was not rescued by overexpression of α-parvin, an important ILK binding partner, although pressure promoted ILK–α-parvin association and translocated both ILK and α-parvin from cytosol to membrane/cytoskeleton. ILK may be a key mediator of mechanotransduced signals in cancer cells and an important therapeutic target to inhibit metastatic cancer cell adhesion.
Highlights
Cell adhesion, an important biological process, plays a pivotal role in cancer metastasis
Extracellular pressure promotes the phosphorylation of AKT1 and this phosphorylation is required for pressure-stimulated cancer cell adhesion [5]
Our present results demonstrated that integrin-linked kinase (ILK), associating with AKT and focal adhesion kinase (FAK) directly or indirectly, mediates pressure-stimulated cancer cell adhesion by regulating the phosphorylation of AKT at Ser473 and FAK, at Tyr397 and 576
Summary
An important biological process, plays a pivotal role in cancer metastasis. Modest 15 mmHg increases in extracellular pressure consistent with these pathophysiologic effects activate an intracellular signaling pathway in cancer cells that stimulates adhesion to matrix proteins and endothelial cells in vitro [1,2,3] and significantly promotes tumor development and impairs tumor-free survival in a transplantable murine tumor model [4]. Forces such as pressure may promote cancer metastasis in shed tumor cells by stimulating the adhesiveness of viable metastasizing tumor cells to distant sites. Extracellular pressure promotes the phosphorylation of AKT1 and this phosphorylation is required for pressure-stimulated cancer cell adhesion [5]
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