Journal Article

Ethanol Enhances Tumor Angiogenesis <i>In Vitro</i> Induced by Low-Dose Arsenic in Colon Cancer Cells Through Hypoxia-Inducible Factor 1 Alpha Pathway

Lei Wang, Young-Ok Son, Songze Ding, Xin Wang, John Andrew Hitron, Amit Budhraja, Jeong-Chae Lee, Qinchen Lin, Pratheeshkumar Poyil, Zhuo Zhang, Jia Luo and Xianglin Shi

in Toxicological Sciences

Volume 130, issue 2, pages 269-280
Published in print December 2012 | ISSN: 1096-6080
Published online August 2012 | e-ISSN: 1096-0929 | DOI:
Ethanol Enhances Tumor Angiogenesis In Vitro Induced by Low-Dose Arsenic in Colon Cancer Cells Through Hypoxia-Inducible Factor 1  Alpha Pathway

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Health effects due to environmental exposure to arsenic are a major global health concern. Arsenic has been known to induce carcinogenesis and enhance tumor development via complex and unclear mechanism. Ethanol is also a well-established risk factor for many malignancies. However, little is known about the effects of coexposure to arsenic and ethanol in tumor development. In this study, we investigate the signaling and angiogenic effect of coexposure of arsenic and ethanol on different colon cancer cell lines. Results show that ethanol markedly enhanced arsenic-induced tumor angiogenesis in vitro. These responses are related to intracellular reactive oxygen species (ROS) generation, NADPH oxidase activation, and upregulation of PI3K/Akt and hypoxia-inducible factor 1 alpha (HIF-1α) signaling. We have also found that ethanol increases the arsenic-induced expression and secretion of angiogenic signaling molecules such as vascular endothelial growth factor, which further confirmed the above observation. Antioxidant enzymes inhibited arsenic/ethanol-induced tumor angiogenesis, demonstrating that the responsive signaling pathways of coexposure to arsenic and ethanol are related to ROS generation. We conclude that ethanol is able to enhance arsenic-induced tumor angiogenesis in colorectal cancer cells via the HIF-1α pathway. These results indicate that alcohol consumption should be taken into consideration in the investigation of arsenic-induced carcinogenesis in arsenic-exposed populations.

Keywords: arsenic; ethanol; reactive oxygen species; hypoxia-inducible factor 1 alpha; tumor angiogenesis

Journal Article.  6698 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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