Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling

Tien Kuo Macus, Zesheng Liu, Yingjie Wei, Yen Chiu Lin-Lee, Shigeru Tatebe, Gordon Mills, Hitoshi Unate

Research output: Contribution to journalArticle

158 Citations (Scopus)

Abstract

The expression of P-glycoprotein encoded by the multidrug resistance (MDR1) gene is associated with the emergence of the MDR phenotype in cancer cells. Human MDR1 and its rodent homolog mdr1a and mdr1b are frequently overexpressed in liver cancers. However, the underlying mechanisms are largely unknown. The hepatocarcinogen 2-acetylaminofluorene (2-AAF) efficiently activates rat mdr1b expression in cultured cells and in Fisher 344 rats. We recently reported that activation of rat mdr1b in cultured cells by 2-AAF involves a cis-activating element containing a NF-κB binding site located -167 to -158 of the rat mdr1b promoter. 2-AAF activates IκB kinase (IKK), resulting in degradation of IκBβ and activation of NF-κB. In this study, we report that 2-AAF could also activate the human MDR1 gene in human hepatoma and embryonic fibroblast 293 cells. Induction of MDR1 by AAF was mediated by DNA sequence located at -6092 which contains a NF-κB binding site. Treating hepatoma cells with 2-AAF activated phosphoinositide 3-kinase (PI3K) and its downstream effectors Rac1, and NAD(P)H oxidase. Transient transfection assays demonstrated that constitutively activated PI3K and Rac1 enhanced the activation of the MDR1 promoter by 2-AAF. Treatment of hepatoma cells with 2-AAF also activated another PI3K downstream effector Akt. Transfection of recombinant encoding a dominant activated Akt also enhanced the activation of MDR1 promoter activation by 2-AAF. These results demonstrated that 2-AAF up-regulates MDR1 expression is mediated by the multiple effectors of the PI3K signaling pathway.

Original languageEnglish (US)
Pages (from-to)1945-1954
Number of pages10
JournalOncogene
Volume21
Issue number13
DOIs
StatePublished - May 21 2002
Externally publishedYes

Fingerprint

2-Acetylaminofluorene
1-Phosphatidylinositol 4-Kinase
Gene Expression
Hepatocellular Carcinoma
Transfection
Cultured Cells
Binding Sites
MDR Genes
NADPH Oxidase
P-Glycoprotein
Liver Neoplasms
Rodentia
Phosphotransferases
Up-Regulation
Fibroblasts
Phenotype

Keywords

  • 2-acetylaminofluorene
  • Akt
  • MDR
  • PI3 kinase
  • Rac

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling. / Macus, Tien Kuo; Liu, Zesheng; Wei, Yingjie; Lin-Lee, Yen Chiu; Tatebe, Shigeru; Mills, Gordon; Unate, Hitoshi.

In: Oncogene, Vol. 21, No. 13, 21.05.2002, p. 1945-1954.

Research output: Contribution to journalArticle

Macus, Tien Kuo ; Liu, Zesheng ; Wei, Yingjie ; Lin-Lee, Yen Chiu ; Tatebe, Shigeru ; Mills, Gordon ; Unate, Hitoshi. / Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling. In: Oncogene. 2002 ; Vol. 21, No. 13. pp. 1945-1954.
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abstract = "The expression of P-glycoprotein encoded by the multidrug resistance (MDR1) gene is associated with the emergence of the MDR phenotype in cancer cells. Human MDR1 and its rodent homolog mdr1a and mdr1b are frequently overexpressed in liver cancers. However, the underlying mechanisms are largely unknown. The hepatocarcinogen 2-acetylaminofluorene (2-AAF) efficiently activates rat mdr1b expression in cultured cells and in Fisher 344 rats. We recently reported that activation of rat mdr1b in cultured cells by 2-AAF involves a cis-activating element containing a NF-κB binding site located -167 to -158 of the rat mdr1b promoter. 2-AAF activates IκB kinase (IKK), resulting in degradation of IκBβ and activation of NF-κB. In this study, we report that 2-AAF could also activate the human MDR1 gene in human hepatoma and embryonic fibroblast 293 cells. Induction of MDR1 by AAF was mediated by DNA sequence located at -6092 which contains a NF-κB binding site. Treating hepatoma cells with 2-AAF activated phosphoinositide 3-kinase (PI3K) and its downstream effectors Rac1, and NAD(P)H oxidase. Transient transfection assays demonstrated that constitutively activated PI3K and Rac1 enhanced the activation of the MDR1 promoter by 2-AAF. Treatment of hepatoma cells with 2-AAF also activated another PI3K downstream effector Akt. Transfection of recombinant encoding a dominant activated Akt also enhanced the activation of MDR1 promoter activation by 2-AAF. These results demonstrated that 2-AAF up-regulates MDR1 expression is mediated by the multiple effectors of the PI3K signaling pathway.",
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AU - Tatebe, Shigeru

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AB - The expression of P-glycoprotein encoded by the multidrug resistance (MDR1) gene is associated with the emergence of the MDR phenotype in cancer cells. Human MDR1 and its rodent homolog mdr1a and mdr1b are frequently overexpressed in liver cancers. However, the underlying mechanisms are largely unknown. The hepatocarcinogen 2-acetylaminofluorene (2-AAF) efficiently activates rat mdr1b expression in cultured cells and in Fisher 344 rats. We recently reported that activation of rat mdr1b in cultured cells by 2-AAF involves a cis-activating element containing a NF-κB binding site located -167 to -158 of the rat mdr1b promoter. 2-AAF activates IκB kinase (IKK), resulting in degradation of IκBβ and activation of NF-κB. In this study, we report that 2-AAF could also activate the human MDR1 gene in human hepatoma and embryonic fibroblast 293 cells. Induction of MDR1 by AAF was mediated by DNA sequence located at -6092 which contains a NF-κB binding site. Treating hepatoma cells with 2-AAF activated phosphoinositide 3-kinase (PI3K) and its downstream effectors Rac1, and NAD(P)H oxidase. Transient transfection assays demonstrated that constitutively activated PI3K and Rac1 enhanced the activation of the MDR1 promoter by 2-AAF. Treatment of hepatoma cells with 2-AAF also activated another PI3K downstream effector Akt. Transfection of recombinant encoding a dominant activated Akt also enhanced the activation of MDR1 promoter activation by 2-AAF. These results demonstrated that 2-AAF up-regulates MDR1 expression is mediated by the multiple effectors of the PI3K signaling pathway.

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