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First published on July 5, 2007; DOI: 10.1124/mol.107.038174

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Received for publication May 16, 2007.
Revised July 3, 2007.
Accepted for publication July 5, 2007.

Induction of Glutathione S-Transferase in IGF Type I Receptor Overexpressed Hepatoma Cells

Jeong Yong Lee 1, Chang Yeob Han 1, Jin Won Yang 1, Christopher Smith 2, Sang Kyum Kim 3, Eva Y-H P Lee 2, Sang Geon Kim 4, Keon Wook Kang 1*

1 BK21 Project Team, College of Pharmacy, Chosun University 2 Departments of Biological Chemistry, University of California at Irvine 3 College of Pharmacy and Research Center for Transgenic Cloned Pigs, Chungnam National University 4 College of Pharmacy, Seoul National University

* Address correspondence to: E-mail: kwkang{at}chosun.ac.kr

Abstract

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 S-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 overexpressions of IGF-IR affect IGF-1-inducible GST expression. GST{alpha} was induced by exposure to IGF-1 in IGF-IR cells but not in cells expressing normal levels of IGF-IR. Furthermore, IR-HCCs 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 XRE in GST{alpha} induction. IGF-1 caused the nuclear translocation of C/EBP{beta}, which might be responsible for the activation of XRE. In addition, IGF-1 increased the activities of PI3-kinase and ERK in IR-HCCs, as determined by the phosphorylations of these kinases. Moreover, the inhibition of PI3-kinase completely abolished the nuclear translocation of C/EBP{beta} and the upregulation of GST{alpha} protein in IGF-IR-overexpressed HCC (IR-HCC) treated with IGF-1. However, specific inhibitors against ERK, JNK or p38 kinase did not alter IGF-1-inducible GST{alpha} expression. These results provide evidence that one of the pathologic consequences of IGF-IR overexpression in HCCs is the potentiation of GST{alpha} inducibility by IGF-1. Moreover, this potentiation of GST may be associated with decreased susceptibility to chemotherapeutic agents such as doxorubicin.


Key words: Glutathione S-transferases, Regulation - transcriptional, Oxidative stress/antioxidants, Resistance




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