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Molecular Pharmacology

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Research ArticleArticle

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

Jeong Yong Lee, Chang Yeob Han, Jin Won Yang, Christopher Smith, Sang Kyum Kim, Eva Y.-H. P. Lee, Sang Geon Kim and Keon Wook Kang
Molecular Pharmacology October 2007, 72 (4) 1082-1093; DOI: https://doi.org/10.1124/mol.107.038174
Jeong Yong Lee
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Chang Yeob Han
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Jin Won Yang
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Christopher Smith
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Sang Kyum Kim
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Eva Y.-H. P. Lee
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Sang Geon Kim
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Keon Wook Kang
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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 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.

Footnotes

  • This work was financially supported by a Korean Research Foundation grant (KRF-2004-E00037).

  • J.Y.L., C.Y.H., and J.W.Y. contributed equally to this work.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.038174.

  • ABBREVIATIONS: HCC, hepatocellular carcinoma cells; ARE, antioxidant response element; BCIP, 5-bromo-4-chloro-3-indoylphosphate; C/EBP, CCAAT/enhancer-binding protein; GST, glutathione transferase; IGF, insulin-like growth factor; IGF-IR, insulin-like growth factor type I receptor; IR-HCC, insulin-like growth factor type I receptor-overexpressed hepatocellular carcinoma cells; NBT, nitroblue tetrazolium; Nrf2, NF-E2-related factor 2; MAP, mitogen-activated protein; PBS, phosphate-buffered saline; PI3-kinase, phosphatidylinositol 3-kinase; ROS, reactive oxygen species; XRE, xenobiotic response element; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; MKK1, mitogen-activated protein kinase kinase 1; GFP, green fluorescent protein; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; DAPI, 4,6-diamidino-2-phenylindole; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; SP600125, anthra(1,9-cd)pyrazol-6(2H)-one 1,9-pyrazoloanthrone.

    • Received May 16, 2007.
    • Accepted July 5, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (4)
Molecular Pharmacology
Vol. 72, Issue 4
1 Oct 2007
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Research ArticleArticle

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

Jeong Yong Lee, Chang Yeob Han, Jin Won Yang, Christopher Smith, Sang Kyum Kim, Eva Y.-H. P. Lee, Sang Geon Kim and Keon Wook Kang
Molecular Pharmacology October 1, 2007, 72 (4) 1082-1093; DOI: https://doi.org/10.1124/mol.107.038174

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Research ArticleArticle

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

Jeong Yong Lee, Chang Yeob Han, Jin Won Yang, Christopher Smith, Sang Kyum Kim, Eva Y.-H. P. Lee, Sang Geon Kim and Keon Wook Kang
Molecular Pharmacology October 1, 2007, 72 (4) 1082-1093; DOI: https://doi.org/10.1124/mol.107.038174
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