Oncotarget

Research Papers:

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

Po-Chun Tseng, Chia-Ling Chen, Yan-Shen Shan and Chiou-Feng Lin _

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Oncotarget. 2016; 7:15150-15160. https://doi.org/10.18632/oncotarget.7750

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Abstract

Po-Chun Tseng1, Chia-Ling Chen2, Yan-Shen Shan1,3, Chiou-Feng Lin4,5

1Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan

2Translational Medicine Center, Taipei Medical University, Taipei 110, Taiwan

3Department of Surgery, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan

4Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan

5Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan

Correspondence to:

Chiou-Feng Lin, e-mail: [email protected]

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-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.


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