Galectin-1 sensitizes carcinoma cells to anoikis via the fibronectin receptor α5β1-integrin

Abstract

Anoikis resistance is a hallmark of transformed epithelial cells. Here, we show that treatment of anoikis-resistant carcinoma cell lines with the endogenous lectin galectin-1 (Gal-1) promoted apoptosis via interaction with the unligated fibronectin receptor a 5 b 1 -integrin. Gal-1 efficiency correlated with expression of a 5 b 1 -integrin, and transfection of the a 5 -subunit into deficient cell lines conferred Gal-1 binding and anoikis stimulation. Furthermore, Gal-1 and the a 5 -and b 1 -integrin subunits co-precipitated in Gal-1-stimulated cells undergoing anoikis. Other members of the galectin family failed to be active. The functional interaction between Gal-1 and a 5 b 1 -integrin was glycan dependent with a2,6-sialylation representing a switch-off signal. Desialylation of cell surface glycans resulted in increased electrophoretic mobility of a 5 b 1 -integrin and facilitated Gal-1 binding and anoikis stimulation. On the level of signaling, Gal-1-stimulated anoikis was prevented by filipin, which impaired the internalization of a 5 b 1 -integrin via cholesterol-enriched microdomains, and by pretreatment with a caspase-8 inhibitor. We propose that Gal-1/ a 5 b 1 -integrin interaction participates in the control of epithelial integrity and integrin sialylation may enable carcinoma cells to evade this Gal-1-dependent control mechanism.

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

“…It is thus conceivable that Gal‐1‐mediated accumulation of these two potent cyclin‐dependent kinase 2 inhibitors may operate also in reactive glial cells, ultimately arresting them in G1 phase of cell cycle. Besides regulation of cell cycle, exogenously added Gal‐1 also exerts effects through interaction with integrins (Astorgues‐Xerri et al, 2014; Moiseeva et al, 2003), such as activating proapoptotic α5β1‐integrin signaling (Sanchez‐Ruderisch et al, 2011). Gal‐1‐induced apoptosis involves several intracellular mediators including the transcription factor AP1 and the downregulation of Bcl2 protein production (Hahn et al, 2004; Rabinovich et al, 2000; Walzel et al, 2000).…”

Regulation of the metastatic cell phenotype by sialylated glycans

“…Each galectin exhibits specificity for certain galactosyl structures, and there is evidence that galectins may selectively bind to distinct glycoproteins. The mechanisms underlying galectin selectivity are still under investigation, although some of the documented binding partners for galectins include integrins [38, 208, 209], EGFR [210], CD45 [211], and TRPV5 [20]. Galectins are secreted by immune (and other) cells, therefore α2-6 sialylation on the tumor cell surface may protect tumor cells from the actions of infiltrating immune cells.…”

Sialic Acids Sweeten a Tumor's Life

“…Amano and colleagues and Sanchez-Ruderisch and colleagues suggested an on/off switch model in which sialylation of the fibronectin receptor a5b1-integrin controls galectin-1-mediated anoikis (22,23). In this model, galectin-1 binds a5b1-integrin following detachment from fibronectin and triggers proapoptotic signals leading to caspase-8 activation and subsequent cell death.…”