Regulation of SHP2 by PTEN/AKT/GSK-3β signaling facilitates IFN-γ resistance in hyperproliferating gastric cancer

Po-Chun Tseng, Wei-Ching Huang, Chia-Ling Chen, Bor-Shyang Sheu, Yan-Shen Shan, Cheng-Chieh Tsai, Chi-Yun Wang, Su-O. Chen, Chia-Yuan Hsieh, Chiou Feng Lin

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Oncogenic activation accompanied by escape from immune surveillance, such as IFN-γ resistance, is critical for cancer cell growth and survival. In this study, we investigated the crosstalk signaling between IFN-γ resistance and signaling of hyperproliferation in gastric cancer cells. IFN-γ inhibited the cell growth of MKN45 cells but not hyperproliferating AGS cells. AGS cells did not respond to IFN-γ because of a decrease in STAT1 but not due to dysfunctional IFN-γ receptors. Signaling of PI3K/AKT, as well as MEK/ERK, was required for the hyperproliferation; notably, PI3K/AKT alone mediated the IFN-γ resistance. Aberrant Src homology-2 domain-containing phosphatase (SHP) 2 determined IFN-γ resistance but unexpectedly had no effects on hyperproliferation or ERK activation. In the IFN-γ resistant cells, inactivation of glycogen synthase kinase (GSK)-3β by PI3K/AKT was important for SHP2 activation but not for hyperproliferation. An imbalance of AKT/GSK-3β/SHP2 caused by a reduction of PTEN was important for the crosstalk between IFN-γ resistance and hyperproliferation. PI3K is constitutively expressed in AGS cells and immunohistochemical staining showed a correlation between hyperproliferation and expression of SHP2 and STAT1 in gastric tumors. These results demonstrate the effects of PTEN/AKT/GSK-3β/SHP2 signaling on IFN-γ resistance in hyperproliferating gastric cancer cells.

Original languageEnglish
Pages (from-to)926-934
Number of pages9
JournalImmunobiology
Volume217
Issue number9
DOIs
Publication statusPublished - Sep 2012
Externally publishedYes

Keywords

  • AKT
  • Gastric cancer
  • GSK-3β
  • Hyperproliferation
  • IFN-γ
  • PTEN
  • SHP2

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Hematology

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