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

// Po-Chun Tseng 1 , Chia-Ling Chen 2 , Yan-Shen Shan 1, 3 , Chiou-Feng Lin 4, 5 1 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan 2 Translational Medicine Center, Taipei Medical University, Taipei 110, Taiwan 3 Department of Surgery, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan 4 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan 5 Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan Correspondence to: Chiou-Feng Lin, e-mail: cflin2014@tmu.edu.tw Keywords: IFN-γ, galectin-3, AKT, GSK-3β, SHP2 Received: May 19, 2015     Accepted: January 22, 2016     Published: February 26, 2016 ABSTRACT Glycogen synthase kinase (GSK)-3β facilitates interferon (IFN)-γ 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-3β inactivation to induce SHP2-activated cellular unresponsiveness to IFN-γ in human gastric cancer AGS cells. This study investigated the potential role of galectin-3, which acts upstream of AKT/GSK-3β/SHP2, in gastric cancer cells. Increasing or decreasing galectin-3 altered IFN-γ signaling. Following cisplatin-induced galectin-3 upregulation, surviving cells showed cellular unresponsiveness to IFN-γ. Galectin-3 induced IFN-γ resistance independent of its extracellular β-galactoside-binding activity. Galectin-3 expression was not regulated by PI3K activation or by a decrease in PTEN. Increased galectin-3 may cause GSK-3β inactivation and SHP2 activation by promoting PDK1-induced AKT phosphorylation at a threonine residue. Overexpression of AKT, inactive GSK-3β R96A , SHP2, or active SHP2 D61A caused cellular unresponsiveness to IFN-γ in IFN-γ-sensitive MKN45 cells. IFN-γ-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-3β/SHP2 signaling, causing cellular unresponsiveness to IFN-γ.