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

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Wang L, Hitron JA, Wise JT, Son YO, Roy RV, Kim D, Dai J, Pratheeshkumar P, Zhang Z, Xu M, Luo J, Shi X

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

Toxicol Appl Pharmacol. 2015 Oct 15;288(2):232-9. doi: 10.1016/j.taap.2015.07.019. Epub 2015 Jul 26.

PubMed ID

26220687 [ View in PubMed

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Abstract

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-kappaB 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-kappaB pathways. These results imply that, as a common dietary factor, ethanol ingestion may be a compounding risk factor for arsenic-induced carcinogenesis/cancer development.