Induction of glutathione transferase in insulin-like growth factor type I receptor-overexpressed hepatoma cells.
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.
Lee
Jeong Yong
JY
College of Pharmacy, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju 501-759, South Korea.
Han
Chang Yeob
CY
Yang
Jin Won
JW
Smith
Christopher
C
Kim
Sang Kyum
SK
Lee
Eva Y-H P
EY
Kim
Sang Geon
SG
Kang
Keon Wook
KW
D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004790:Enzyme Induction; D005982:Glutathione Transferase / Q000096:biosynthesis*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D005982:Glutathione Transferase; D011494:Protein Kinases; D017526:Receptor, IGF Type 1