RRC ID 63502
Author Tseng PC, Chen CL, Shan YS, Lin CF.
Title An increase in galectin-3 causes cellular unresponsiveness to IFN-γ-induced signal transduction and growth inhibition in gastric cancer cells.
Journal Oncotarget
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-3βR96A, SHP2, or active SHP2D61A 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.
Volume 7(12)
Pages 15150-60
Published 2016-3-22
DOI 10.18632/oncotarget.7750
PII 7750
PMID 26934444
PMC PMC4924776
MeSH Antiviral Agents / pharmacology Apoptosis / drug effects Biomarkers, Tumor / genetics Biomarkers, Tumor / metabolism Cell Proliferation / drug effects Drug Resistance, Neoplasm* Galectin 3 / genetics Galectin 3 / metabolism* Gene Expression Regulation, Neoplastic / drug effects* Glycogen Synthase Kinase 3 beta / genetics Glycogen Synthase Kinase 3 beta / metabolism Humans Interferon-gamma / pharmacology* Phosphorylation / drug effects Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism Proto-Oncogene Proteins c-akt / genetics Proto-Oncogene Proteins c-akt / metabolism Signal Transduction / drug effects* Stomach Neoplasms / drug therapy Stomach Neoplasms / metabolism Stomach Neoplasms / pathology* Tumor Cells, Cultured
IF 5.168
Human and Animal Cells MKN45(RCB1001)