Tumor-promoting and pro-angiogenic effects of roxarsone via VEGFR2/PLCγ/PKC signaling
Tumor-promoting and pro-angiogenic effects of roxarsone via VEGFR2/PLCγ/PKC signaling
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DOI：
10.1016/j.cbi.2018.07.012
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发表时间：
2018-08-25
影响因子：
5.1
通讯作者：
Zhang, Yumei
中科院分区：
文献类型：
--
作者：
Pang, Yanhua;Wang, Kai;Zhang, Yumei
洛克沙胂是一种用于畜禽生产的有机砷饲料添加剂，被释放到环境中，对人类健康构成风险。已知其具有促肿瘤作用，其由促血管生成因子如血管内皮生长因子（VEGF）及其受体（VEGFR）引起。然而，关于可能涉及的其他信号分子的信息很少。本研究旨在探讨PLC γ/PKC信号在洛克沙胂诱导的小鼠B16-F10黑色素瘤异种移植模型和大鼠血管内皮细胞（EC）血管生成中的作用。结果显示，5 mg/kg和25 mg/kg洛克沙胂可明显增加C57 BL/6小鼠B16-F10移植瘤的重量和体积，并呈剂量依赖性增加PLC γ/ PKC磷酸化水平。VEGFR 2抑制剂SU 5416可显著抑制洛克沙胂诱导的肿瘤生长。此外，观察到1.0 μ mol/L洛克沙胂处理大鼠EC在MTT测定中的光密度率、在增殖测定中的BrdU阳性细胞数、在划痕试验中的迁移距离和在管形成测定中形成的网孔数显著增加。此外，与对照组相比，1.0 μ mol/L洛克沙胂处理组PLC γ/PKC磷酸化水平显著升高。PLC γ抑制剂U 73122能显著对抗1.0 μ mol/L洛克沙胂对EC的抑制作用。Roxarsone能够促进小鼠B16-F10异种移植物的生长和血管EC中的管形成。此外，VEGFR 2/PLC γ/PKC信号转导可能在洛克沙胂诱导的体内和体外血管生成中发挥调节作用。
Roxarsone is an organoarsenic feed additive used in livestock and poultry production that is released into the environment, where it poses a risk to human health. It is known to have a tumor-promoting effect that is brought about by pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and it receptors (VEGFR). However, little information is available about the other signaling molecules that could be involved. This study aims to investigate the role of PLC gamma/PKC signaling in roxarsone-induced angiogenesis in a mouse B16-F10 melanoma xenograft model and rat vascular endothelial cells (ECs). Results showed treatment with 5 mg/kg and 25 mg/kg roxarsone resulted in an obvious increase in the weight and volume of B16-F10 xenografts and PLC gamma/ PKC phosphorylation in a dose-dependent manner in C57BL/6 mice. SU5416, a VEGFR2 inhibitor, significantly attenuated the tumor growth induced by roxarsone. Further, 1.0 mu mol/L roxarsone treatment in rat ECs was observed to significantly increase the optical density rate in the MTT assay, the number of BrdU-positive cells in the proliferation assay, the migration distance in the scratch test, and the number of meshes formed in the tube formation assay. In addition, treatment with 1.0 mu mol/L roxarsone was associated with significantly higher phosphorylation of PLC gamma/PKC than the control treatment. U73122, a PLC gamma inhibitor, was found significantly to combat the effects of 1.0 mu mol/L roxarsone on the ECs. Roxarsone is capable of promoting the growth of mouse B16-F10 xenografts and tube formation in vascular ECs. Moreover, VEGFR2/PLC gamma/PKC signaling may play a regulatory role in in vivo and in vitro roxarsone-induced angiogenesis.