Induction of glutathione transferase in insulin-like growth factor type I receptor-overexpressed hepatoma cells

Cited 21 time in Web of Science Cited 23 time in Scopus

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

Issue Date
American Society for Pharmacology and Experimental Therapeutics (ASPET)
Mol Pharmacol. 2007 Oct;72(4):1082-93. Epub 2007 Jul 5.
Antineoplastic Agents/pharmacologyCarcinoma, Hepatocellular/enzymology/*metabolism/pathologyCell DivisionCell Line, TumorDoxorubicin/pharmacologyEnzyme InductionGlutathione Transferase/*biosynthesisHumansLiver Neoplasms/enzymology/*metabolism/pathologyProtein Kinases/metabolismReactive Oxygen Species/metabolismReceptor, IGF Type 1/genetics/*metabolism
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. GSTalpha 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 GSTalpha induction. IGF-1 caused the nuclear translocation of CCAAT/enhancer-binding protein beta (C/EBPbeta), 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/EBPbeta and the up-regulation of GSTalpha 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 GSTalpha expression. These results provide evidence that one of the pathological consequences of IGF-IR overexpression in HCCs is the potentiation of GSTalpha inducibility by IGF-1. Moreover, this potentiation of GST may be associated with decreased susceptibility to chemotherapeutic agents such as doxorubicin.
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College of Medicine/School of Medicine (의과대학/대학원)Program in Clinical Pharmacology (협동과정-임상약리학전공)Journal Papers (저널논문_협동과정-임상약리학전공)
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