The α5β1 fibronectin receptor sensitizes carcinoma cells to Galectin–1 mediated anoikis

Resistance to anoikis, an apoptosis program initiated by loss of contact to the extracellular matrix, is a hallmark of transformed epithelial cells. In previous studies, we could restore anoikis in Capan–1 human pancreatic cancer cells by restitution of p16 via mechanisms that required the induction of the fibronectin receptor α5β1. To identify potential mediators in the p16-dependent pathway that induces anoikis, we conducted a gene expression profiling. Among almost 2000 genes screened, the mRNA for the lectin Galectin–1 was one of the most prominently induced, defining this gene as a novel transcriptional target of p16. Addressing the functional role of Galectin–1 in anoikis, we demonstrated that overexpression of Galectin–1 was in Capan–1 cells sufficient to reestablish and also required for p16-mediated anoikis. Furthermore, exogenous addition of Galectin–1 equally promoted anoikis in a broad spectrum of cell lines that express the α5β1 fibronectin receptor. Finally, transfection of the α5 integrin subunit cDNA into α5-deficient Galectin–1 resistant cell lines increased Galectin–1 binding and rendered cells susceptible to Galectin–1 stimulated anoikis. Exploring the mechanisms of Galectin–1 mediated anoikis induction, we detected a rapid activation of α5β1-associated caspase–8 upon Galectin–1 binding to the fibronectin receptor. In summary, we identified Galectin–1 as a novel modulator of anchorage-independent survival, which is transcriptionally controlled by p16. The mechanism of anoikis stimulation by Galectin–1 encompasses selective interaction with the α5β1 fibronectin receptor and subsequent activation of caspase–8. Thus, Galectin–1 emerges as a crucial regulator of epithelial integrity. A potential therapeutical application of Galectin–1 is a matter of future research.