The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel

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  • Liu, Qian
    • Affiliation: Gillings School of Global Public Health, Department of Environmental Sciences and Engineering
  • Zhang, Hao
    • Other Affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA; Department of Environmental Health, School of Public Health, Fudan University, Shanghai 200032, P.R. China
  • Smeester, Lisa
    • Affiliation: Gillings School of Global Public Health, Department of Environmental Sciences and Engineering
  • Zou, Fei
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
  • Kesic, Matthew J
    • Affiliation: School of Medicine, Center for Environmental Medicine, Asthma and Lung Biology
  • Jaspers, Ilona
    • Affiliation: School of Medicine, Center for Environmental Medicine, Asthma and Lung Biology
  • Pi, Jingbo
    • Other Affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA
  • Fry, Rebecca
    • Affiliation: Gillings School of Global Public Health, Department of Environmental Sciences and Engineering
Abstract
  • Abstract Background Drinking water contaminated with inorganic arsenic is associated with increased risk for different types of cancer. Paradoxically, arsenic trioxide can also be used to induce remission in patients with acute promyelocytic leukemia (APL) with a success rate of approximately 80%. A comprehensive study examining the mechanisms and potential signaling pathways contributing to the anti-tumor properties of arsenic trioxide has not been carried out. Methods Here we applied a systems biology approach to identify gene biomarkers that underlie tumor cell responses to arsenic-induced cytotoxicity. The baseline gene expression levels of 14,500 well characterized human genes were associated with the GI50 data of the NCI-60 tumor cell line panel from the developmental therapeutics program (DTP) database. Selected biomarkers were tested in vitro for the ability to influence tumor susceptibility to arsenic trioxide. Results A significant association was found between the baseline expression levels of 209 human genes and the sensitivity of the tumor cell line panel upon exposure to arsenic trioxide. These genes were overlayed onto protein-protein network maps to identify transcriptional networks that modulate tumor cell responses to arsenic trioxide. The analysis revealed a significant enrichment for the oxidative stress response pathway mediated by nuclear factor erythroid 2-related factor 2 (NRF2) with high expression in arsenic resistant tumor cell lines. The role of the NRF2 pathway in protecting cells against arsenic-induced cell killing was validated in tumor cells using shRNA-mediated knock-down. Conclusions In this study, we show that the expression level of genes in the NRF2 pathway serve as potential gene biomarkers of tumor cell responses to arsenic trioxide. Importantly, we demonstrate that tumor cells that are deficient for NRF2 display increased sensitivity to arsenic trioxide. The results of our study will be useful in understanding the mechanism of arsenic-induced cytotoxicity in cells, as well as the increased applicability of arsenic trioxide as a chemotherapeutic agent in cancer treatment.
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  • Article
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  • In Copyright
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  • Qian Liu et al.; licensee BioMed Central Ltd.
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Journal title
  • BMC Medical Genomics
Journal volume
  • 3
Journal issue
  • 1
Page start
  • 37
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1755-8794
Bibliographic citation
  • BMC Medical Genomics. 2010 Aug 13;3(1):37
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • July 16, 2016

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