Abstract

Expression of the multidrug resistance gene (MDR1) is frequently upregulated in human hepatocellular carcinomas (HCC). In rodents, MDR1 homologous mdr1a and mdr1b are consistently upregulated during heptocarcinogenesis in many different carcinogenic programs. These observations suggest that activation of mdr1 expression and hepatocarcinogenetic programs may share overlapping pathways. As a first step to test this hypothesis, we investigated the activation mechanisms of rat mdr1b in cultured cells induced by hepatocarcinogen 2-acetylaminofluorene (AAF). We found that the NF-KB signal is involved in the upregulation of mdr1b expression. Activation of NF-KB and elevated expression of MDR1 by the carcinogen also can be seen in human hepatoma cells. The goals of our research are to determine how NF-KB signaling is activated for the upregulation of mdr1b gene expression during hepatocarcinogenesis, and whetheractivation of this signal plays a role in the development of liver cancer.
Three specific aims are proposed.
The first aim i s to determine the upstream and downstream signals of NF-KB in AAF-induced mdr1b expression. The possible involvement of phosphoinosite 3 kinase (PI3K) and Akt as upstream signal and transcriptional coactivators as downstream signal in chromatin will be investigated.
The second aim i s to determine whether the same signal also involved in the upregulation of mdr1b regulation in vivo. Adenoviral vectors will be used to deliver inhibitors of the NF-KB signal to the liver to investigate whether modulation of this signal would alter the expression of mdr1b. The last aim is to investigate whether NF-KB plays a role in hepatocarcinogenesis. Nontoxic adenoviral vector will be used to target recombinant DNA constructs to the liver to determine whether intervention of NF-KB signal would affect the rate of AAF-induced liver cancer development. We hope from this research, which includes in vitro cell culture and in vivo animal and tumor models, to gain important molecular insights into the genetic resolution of drug resistance and hepatocarcinogenesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA072404-04A2
Application #
6398108
Study Section
Special Emphasis Panel (ZRG1-ET-2 (04))
Program Officer
Forry, Suzanne L
Project Start
1997-05-09
Project End
2005-08-31
Budget Start
2001-09-27
Budget End
2002-08-31
Support Year
4
Fiscal Year
2001
Total Cost
$280,125
Indirect Cost

  Institution

Name
University of Texas MD Anderson Cancer Center
Department
Pathology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Kuo, Macus Tien (2009) Redox regulation of multidrug resistance in cancer chemotherapy: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal 11:99-133
Aiba, Isamu; Hossain, Anwar; Kuo, Macus Tien (2008) Elevated GSH level increases cadmium resistance through down-regulation of Sp1-dependent expression of the cadmium transporter ZIP8. Mol Pharmacol 74:823-33
Chen, Helen H W; Song, Im-Sook; Hossain, Anwar et al. (2008) Elevated glutathione levels confer cellular sensitization to cisplatin toxicity by up-regulation of copper transporter hCtr1. Mol Pharmacol 74:697-704
Song, Im-Sook; Chen, Helen H W; Aiba, Isamu et al. (2008) Transcription factor Sp1 plays an important role in the regulation of copper homeostasis in mammalian cells. Mol Pharmacol 74:705-13
Kuo, Macus Tien; Chen, Helen H W; Song, Im-Sook et al. (2007) The roles of copper transporters in cisplatin resistance. Cancer Metastasis Rev 26:71-83
Kuo, M Tien (2007) Roles of multidrug resistance genes in breast cancer chemoresistance. Adv Exp Med Biol 608:23-30
Kuo, M Tien; Wei, Yingjie; Yang, Xinlin et al. (2006) Association of fragile site-associated (FSA) gene expression with epithelial differentiation and tumor development. Biochem Biophys Res Commun 340:887-93
Wei, Yingjie; Lin-Lee, Yen-Chiu; Yang, Xinlin et al. (2006) Molecular cloning of Chinese hamster 1q31 chromosomal fragile site DNA that is important to mdr1 gene amplification reveals a novel gene whose expression is associated with spermatocyte and adipocyte differentiation. Gene 372:44-52
Tien Kuo, M; Savaraj, Niramol (2006) Roles of reactive oxygen species in hepatocarcinogenesis and drug resistance gene expression in liver cancers. Mol Carcinog 45:701-9
Song, Im-Sook; Tatebe, Shigeru; Dai, Wenping et al. (2005) Delayed mechanism for induction of gamma-glutamylcysteine synthetase heavy subunit mRNA stability by oxidative stress involving p38 mitogen-activated protein kinase signaling. J Biol Chem 280:28230-40

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