TY - JOUR T1 - Induction of Glutathione Transferase in Insulin-Like Growth Factor Type I Receptor-Overexpressed Hepatoma Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1082 LP - 1093 DO - 10.1124/mol.107.038174 VL - 72 IS - 4 AU - Jeong Yong Lee AU - Chang Yeob Han AU - Jin Won Yang AU - Christopher Smith AU - Sang Kyum Kim AU - Eva Y.-H. P. Lee AU - Sang Geon Kim AU - Keon Wook Kang Y1 - 2007/10/01 UR - http://molpharm.aspetjournals.org/content/72/4/1082.abstract N2 - Insulin-like growth factor type I receptor (IGF-IR) is frequently overexpressed in human hepatocellular carcinoma cells (HCC), and this overexpression has been correlated with increased tumor growth. The protective response of HCC to reactive oxygen species (ROS) produced by chemotherapeutic agents is mediated with the induction of phase II detoxifying genes including glutathione transferase (GST). To understand the roles of IGF-IR overexpression in HCC in terms of its detoxifying effect on ROS and conferred resistance to chemotherapy, we analyzed whether IGF-IR overexpressions affect IGF-1-inducible GST expression. GSTα was induced by exposure to IGF-1 in IGF-IR cells but not in cells expressing normal levels of IGF-IR. Furthermore, IGF-IR-overexpressed HCCs (IR-HCC) are more resistant to doxorubicin than control HCC cells, which was associated with the increased GST induction by IGF-1. Molecular analyses using GSTA2 promoter supported the involvement of xenobiotic response element (XRE) in GSTα induction. IGF-1 caused the nuclear translocation of CCAAT/enhancer-binding protein β (C/EBPβ), which might be responsible for XRE activation. In addition, IGF-1 increased the activities of phosphatidylinositol 3-kinase (PI3-kinase) and extracellular signal-regulated kinase in IR-HCCs. Moreover, the inhibition of PI3-kinase completely abolished the nuclear translocation of C/EBPβ and the up-regulation of GSTα protein in IR-HCC treated with IGF-1. However, specific inhibitors against extracellular signal-regulated kinase, c-Jun N-terminal kinase, or p38 kinase did not alter IGF-1-inducible GSTα expression. These results provide evidence that one of the pathological consequences of IGF-IR overexpression in HCCs is the potentiation of GSTα inducibility by IGF-1. Moreover, this potentiation of GST may be associated with decreased susceptibility to chemotherapeutic agents such as doxorubicin. The American Society for Pharmacology and Experimental Therapeutics ER -