REGULATION OF MDR GENE EXPRESSION IN LIVER CANCERS

Summary

Principal Investigator: MACUS KUO
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 is 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 is 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 Period: 1997-05-09 - 2007-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Delayed mechanism for induction of gamma-glutamylcysteine synthetase heavy subunit mRNA stability by oxidative stress involving p38 mitogen-activated protein kinase signaling
    Im Sook Song
    Department of Molecular Pathology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    J Biol Chem 280:28230-40. 2005
  2. pmc Elevated GSH level increases cadmium resistance through down-regulation of Sp1-dependent expression of the cadmium transporter ZIP8
    Isamu Aiba
    Department of Molecular Pathology, M D Anderson Cancer Center, Houston, TX 77054, USA
    Mol Pharmacol 74:823-33. 2008
  3. pmc Elevated glutathione levels confer cellular sensitization to cisplatin toxicity by up-regulation of copper transporter hCtr1
    Helen H W Chen
    Department of Molecular Pathology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Mol Pharmacol 74:697-704. 2008
  4. pmc Transcription factor Sp1 plays an important role in the regulation of copper homeostasis in mammalian cells
    Im Sook Song
    Department of Molecular Pathology, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
    Mol Pharmacol 74:705-13. 2008
  5. ncbi Roles of multidrug resistance genes in breast cancer chemoresistance
    M Tien Kuo
    Department of Molecular Pathology, Unit 89, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77030, USA
    Adv Exp Med Biol 608:23-30. 2007
  6. ncbi The roles of copper transporters in cisplatin resistance
    Macus Tien Kuo
    Department of Molecular Pathology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Cancer Metastasis Rev 26:71-83. 2007
  7. ncbi Roles of reactive oxygen species in hepatocarcinogenesis and drug resistance gene expression in liver cancers
    M Tien Kuo
    Department of Molecular Pathology, The University of Texas M D Anderson Cancer Center, Houston, 77030, USA
    Mol Carcinog 45:701-9. 2006
  8. ncbi 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
    Yingjie Wei
    Department of Molecular Pathology, Unit 89, The University of Texas M D Anderson Cancer Center, 7435 Fannin Street, Houston, Texas 77030, USA
    Gene 372:44-52. 2006
  9. ncbi Association of fragile site-associated (FSA) gene expression with epithelial differentiation and tumor development
    M Tien Kuo
    Department of Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Street, Houston, TX 77030, USA
    Biochem Biophys Res Commun 340:887-93. 2006
  10. ncbi Redox regulation of matrix metalloproteinase gene family in small cell lung cancer cells
    Niramol Savaraj
    Hematology Oncology Section, Department of Medicine, VA Medical Center, University of Miami School of Medicine, Miami, FL 33125, USA
    Free Radic Res 39:373-81. 2005

Scientific Experts

  • MACUS KUO
  • N Savaraj
  • Im Sook Song
  • Isamu Aiba
  • Helen H W Chen
  • Anwar Hossain
  • Zheng D Liang
  • Leo W J Klomp
  • Yingjie Wei
  • M Tien Kuo
  • Wenping Dai
  • Yoshiaki Yamane
  • Zahid H Siddik
  • Jia Lu
  • Lily Y H Wu
  • Min Koo Choi
  • Yen Chiu Lin-Lee
  • Lynn Feun
  • Sheng Zhao
  • Xinlin Yang
  • Feyruz V Rassool
  • George W Elgart
  • Shigeru Tatebe

Detail Information

Publications11

  1. ncbi Delayed mechanism for induction of gamma-glutamylcysteine synthetase heavy subunit mRNA stability by oxidative stress involving p38 mitogen-activated protein kinase signaling
    Im Sook Song
    Department of Molecular Pathology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    J Biol Chem 280:28230-40. 2005
    ....
  2. pmc Elevated GSH level increases cadmium resistance through down-regulation of Sp1-dependent expression of the cadmium transporter ZIP8
    Isamu Aiba
    Department of Molecular Pathology, M D Anderson Cancer Center, Houston, TX 77054, USA
    Mol Pharmacol 74:823-33. 2008
    ..More important, our results reveal a new mechanism by which elevated GSH levels confer cadmium resistance by down-regulation of ZIP8 expression through the suppression of Sp1...
  3. pmc Elevated glutathione levels confer cellular sensitization to cisplatin toxicity by up-regulation of copper transporter hCtr1
    Helen H W Chen
    Department of Molecular Pathology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Mol Pharmacol 74:697-704. 2008
    ..These findings also have important implications in that modulation of the intracellular copper pool may be a novel strategy for improving chemotherapeutic efficacy of platinum-based antitumor agents...
  4. pmc Transcription factor Sp1 plays an important role in the regulation of copper homeostasis in mammalian cells
    Im Sook Song
    Department of Molecular Pathology, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
    Mol Pharmacol 74:705-13. 2008
    ..Our results demonstrate that mammalian copper homeostasis is maintained at the hCtr1 mRNA level, which is regulated by the Sp1 transcription factor...
  5. ncbi Roles of multidrug resistance genes in breast cancer chemoresistance
    M Tien Kuo
    Department of Molecular Pathology, Unit 89, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77030, USA
    Adv Exp Med Biol 608:23-30. 2007
    ..These studies may lead to novel strategies for improving chemotherapeutic efficacies through targeted interventions of these ABC transporters...
  6. ncbi The roles of copper transporters in cisplatin resistance
    Macus Tien Kuo
    Department of Molecular Pathology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Cancer Metastasis Rev 26:71-83. 2007
    ....
  7. ncbi Roles of reactive oxygen species in hepatocarcinogenesis and drug resistance gene expression in liver cancers
    M Tien Kuo
    Department of Molecular Pathology, The University of Texas M D Anderson Cancer Center, Houston, 77030, USA
    Mol Carcinog 45:701-9. 2006
    ..In this review, we present compelling evidence to support the hypothesis that ROS play important roles in hepatocarcinogenesis and the associated upregulation of drug resistance gene expression...
  8. ncbi 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
    Yingjie Wei
    Department of Molecular Pathology, Unit 89, The University of Texas M D Anderson Cancer Center, 7435 Fannin Street, Houston, Texas 77030, USA
    Gene 372:44-52. 2006
    ..Our results suggest that the Chinese hamster 1q31 fragile site has many important functions including regulation of mdr1 amplification and differentiation of adipocytes and spermatocytes...
  9. ncbi Association of fragile site-associated (FSA) gene expression with epithelial differentiation and tumor development
    M Tien Kuo
    Department of Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Street, Houston, TX 77030, USA
    Biochem Biophys Res Commun 340:887-93. 2006
    ..Moreover, levels of FSA expression are downregulated in tumors of these tissue origins. These results suggest that FSA also plays important roles in regulating mammalian epithelial growth and differentiation and tumor development...
  10. ncbi Redox regulation of matrix metalloproteinase gene family in small cell lung cancer cells
    Niramol Savaraj
    Hematology Oncology Section, Department of Medicine, VA Medical Center, University of Miami School of Medicine, Miami, FL 33125, USA
    Free Radic Res 39:373-81. 2005
    ..These results bear implication that antioxidant modulation of antitumor progression may be contributed at least in part by the downregulation of a subset of metrix metalloproteins...
  11. pmc Redox regulation of multidrug resistance in cancer chemotherapy: molecular mechanisms and therapeutic opportunities
    Macus Tien Kuo
    Department of Molecular Pathology Unit 951, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Antioxid Redox Signal 11:99-133. 2009
    ..Finally, the roles of redox signaling in the maintenance and evolution of cancer stem cells and their implications in the development of intrinsic and acquired multidrug resistance in cancer chemotherapy are discussed...