An increase in galectin-3 causes cellular unresponsiveness to IFN-γ-induced signal transduction and growth inhibition in gastric cancer cells

Glycogen synthase kinase (GSK)-3 beta facilitates interferon (IFN)-gamma signaling by inhibiting Src homology-2 domain-containing phosphatase (SHP) 2. Mutated phosphoinositide 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) cause AKT activation and GSK-3 beta inactivation to induce SHP2-activated cellular unresponsiveness to IFN-gamma in human gastric cancer AGS cells. This study investigated the potential role of galectin-3, which acts upstream of AKT/GSK-3 beta/SHP2, in gastric cancer cells. Increasing or decreasing galectin-3 altered IFN-gamma signaling. Following cisplatin-induced galectin-3 upregulation, surviving cells showed cellular unresponsiveness to IFN-gamma. Galectin-3 induced IFN-gamma resistance independent of its extracellular beta-galactoside-binding activity. Galectin-3 expression was not regulated by PI3K activation or by a decrease in PTEN. Increased galectin-3 may cause GSK-3 beta inactivation and SHP2 activation by promoting PDK1-induced AKT phosphorylation at a threonine residue. Overexpression of AKT, inactive GSK-3 beta(R96A), SHP2, or active SHP2(D61A) caused cellular unresponsiveness to IFN-gamma in IFN-gamma-sensitive MKN45 cells. IFN-gamma-induced growth inhibition and apoptosis in AGS cells were observed until galectin-3 expression was downregulated. These results demonstrate that an increase in galectin-3 facilitates AKT/GSK-3 beta/SHP2 signaling, causing cellular unresponsiveness to IFN-gamma.