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Induction of Glutathione Transferase in Insulin-Like Growth Factor Type I Receptor-Overexpressed Hepatoma Cells

BK21 Project Team, College of Pharmacy, Chosun University, Gwangju, South Korea (J.Y.L., C.Y.H., J.W.Y., K.W.K.); Departments of Biological Chemistry/Developmental and Cell Biology, University of California at Irvine, Irvine, California (E.Y.H.-P.L., C.S.); College of Pharmacy and Research Center for Transgenic Cloned Pigs, Chungnam National University, South Korea (S.K.K.); and College of Pharmacy, Seoul National University, Seoul, South Korea (S.G.K.)

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. GST 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 GST 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 GST 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 GST expression. These results provide evidence that one of the pathological consequences of IGF-IR overexpression in HCCs is the potentiation of GST inducibility by IGF-1. Moreover, this potentiation of GST may be associated with decreased susceptibility to chemotherapeutic agents such as doxorubicin.

Address correspondence to: Dr. Keon Wook Kang, College of Pharmacy, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju 501-759, South Korea; E-mail: kwkang{at}chosun.ac.kr