Ethanol enhances arsenic-induced cyclooxygenase-2 expression via both NFAT and NF-κB signalings in colorectal cancer cells

Lei Wang, John Andrew Hitron, James T.F. Wise, Young Ok Son, Ram Vinod Roy, Donghern Kim, Jin Dai, Poyil Pratheeshkumar, Zhuo Zhang, Mei Xu, Jia Luo, Xianglin Shi

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Arsenic is a known carcinogen to humans, and chronic exposure to environmental arsenic is a worldwide health concern. As a dietary factor, ethanol carries a well-established risk for malignancies, but the effects of co-exposure to arsenic and ethanol on tumor development are not well understood. In the present study, we hypothesized that ethanol would enhance the function of an environmental carcinogen such as arsenic through increase in COX-2 expression. Our in vitro results show that ethanol enhanced arsenic-induced COX-2 expression. We also show that the increased COX-2 expression associates with intracellular ROS generation, up-regulated AKT signaling, with activation of both NFAT and NF-κB pathways. We demonstrate that antioxidant enzymes have an inhibitory effect on arsenic/ethanol-induced COX-2 expression, indicating that the responsive signaling pathways from co-exposure to arsenic and ethanol relate to ROS generation. In vivo results also show that co-exposure to arsenic and ethanol increased COX-2 expression in mice. We conclude that ethanol enhances arsenic-induced COX-2 expression in colorectal cancer cells via both the NFAT and NF-κB pathways. These results imply that, as a common dietary factor, ethanol ingestion may be a compounding risk factor for arsenic-induced carcinogenesis/cancer development.

Original languageEnglish
Pages (from-to)232-239
Number of pages8
JournalToxicology and Applied Pharmacology
Issue number2
StatePublished - Oct 15 2015

Bibliographical note

Funding Information:
We would like to thank Hong Lin for her technical help. This work was supported by the National Institutes of Health [ R01ES021771 , R01ES025515 , R01ES020870 , and R01ES017244 ].

Publisher Copyright:
© 2015 .


  • Arsenic
  • COX-2
  • Ethanol
  • NF-κB
  • NFAT

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology


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