Roxarsone Promotes Glycolysis and Angiogenesis by Inducing Hypoxia-Inducible Factor-1α In Vitro and In Vivo.

Abstract

Roxarsone (Rox) is an organic arsenic compound used as a feed additive to promote animal growth. The release of Rox into the environment poses risks to human health. Rox demonstrated tumor-promoting and proangiogenic effects in xenograft models. Increasing studies revealed the tight relationship among angiogenesis, carcinogenesis, tumorigenesis, and glycolysis. Glycolysis, via hypoxia-inducible factor-1α (HIF-1α), controls vascular endothelial cell (VEC) growth. To date, there has been no literature report on the effect of Rox on HIF-1α-dependent glycolysis. Herein, we report that Rox promoted glycolysis in rat VECs, as shown by the increased adenosine triphosphate production, the lactic acid release, the activity and content of aldolase (ALD), and the expression levels of ALD A and glucose transporter 1 (GLUT1). Rox also increased the cellular levels of HIF-1α. Treatment with the HIF-1α inhibitor YC-1 reversed Rox-increased ALD A and GLUT1 levels and attenuated Rox-induced VEC viability, suggesting that Rox-induced HIF-1α contributes to the glycolytic and angiogenic effects of Rox. Rox also promoted tumor growth and angiogenesis and increased the levels of ALD A, GLUT1, and HIF-1α in the tumor tissue of a mouse xenograft model, whereas these effects were abolished using YC-1. Our findings indicated that Rox induces HIF-1α in VECs to promote glycolysis and angiogenesis thus enhancing the tumor growth.