Chen Xin, Zhang Meng, Chen Linzhongri, Zhou Zhiqiang, Chen Binlin, Wang Cunkai, Xie Yang, Zhang Yumei
Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 Jiangsu, China.
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 Jiangsu, China.
ACS Omega. 2021 Mar 30;6(14):9559-9566. doi: 10.1021/acsomega.1c00072. eCollection 2021 Apr 13.
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.
洛克沙胂（Rox）是一种有机砷化合物，用作饲料添加剂以促进动物生长。Rox释放到环境中会对人类健康构成风险。Rox在异种移植模型中表现出促肿瘤和促血管生成作用。越来越多的研究揭示了血管生成、致癌作用、肿瘤发生和糖酵解之间的紧密关系。糖酵解通过缺氧诱导因子-1α（HIF-1α）控制血管内皮细胞（VEC）的生长。迄今为止，尚无关于Rox对HIF-1α依赖性糖酵解影响的文献报道。在此，我们报告Rox促进大鼠VECs中的糖酵解，表现为三磷酸腺苷生成增加、乳酸释放增加、醛缩酶（ALD）活性和含量增加以及ALD A和葡萄糖转运蛋白1（GLUT1）的表达水平增加。Rox还增加了细胞内HIF-1α的水平。用HIF-1α抑制剂YC-1处理可逆转Rox增加的ALD A和GLUT1水平，并减弱Rox诱导的VEC活力，表明Rox诱导的HIF-1α促成了Rox的糖酵解和血管生成作用。Rox还促进小鼠异种移植模型肿瘤组织中的肿瘤生长和血管生成，并增加ALD A、GLUT1和HIF-1α的水平，而使用YC-1可消除这些作用。我们的研究结果表明，Rox在VECs中诱导HIF-1α以促进糖酵解和血管生成，从而增强肿瘤生长。
