Journal Article
Ethanol enhances tumor angiogenesis in vitro induced by low-dose arsenic in colon cancer cells through hypoxia-inducible factor 1 alpha pathway
Wang, L; Son, Y-O; Ding, S; Wang, X; Hitron, JA; Budhraja, A; Lee, J-C; Lin, Q; Poyil, P; Zhang, Z; Luo, J; Shi, X
Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929
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 co-exposure to arsenic and ethanol in tumor development. In this study, we investigate the signaling and angiogenic effect of co-exposure 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, NAPDH oxidase activation, and up-regulation of PI3K/AKT and hypoxia-inducible factor 1 alpha (HIF-1α) signaling. We have also found that ethanol increase the arsenic-induced expression and secretion of angiogenic signaling molecules such as vascular endothelial growth factor (VEGF), which further confirmed the above observation. Antioxidant enzymes inhibited arsenic/ethanol-induced tumor angiogenesis, demonstrating that the responsive signaling pathways of co-exposure 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.
arsenic; ethanol; reactive oxygen species; hypoxia-inducible factor 1 alpha; tumor angiogenesis
