Regulation of SHP2 by PTEN/AKT/GSK-3ß signaling facilitates IFN-γ resistance in hyperproliferating gastric cancer.
Immunobiology
; 217(9): 926-34, 2012 Sep.
Article
em En
| MEDLINE
| ID: mdl-22325465
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)-3ß by PI3K/AKT was important for SHP2 activation but not for hyperproliferation. An imbalance of AKT/GSK-3ß/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-3ß/SHP2 signaling on IFN-γ resistance in hyperproliferating gastric cancer cells.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Gástricas
/
Interferon gama
/
Resistencia a Medicamentos Antineoplásicos
/
Quinase 3 da Glicogênio Sintase
/
PTEN Fosfo-Hidrolase
/
Proteínas Proto-Oncogênicas c-akt
/
Proteína Tirosina Fosfatase não Receptora Tipo 11
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article