Methylseleninic Acid Provided at Nutritional Selenium Levels Inhibits Angiogenesis by Down-regulating Integrin β3 Signaling.
Methylseleninic Acid Provided at Nutritional Selenium Levels Inhibits Angiogenesis by Down-regulating Integrin β3 Signaling.
复制标题
营养硒水平的甲基硒酸通过下调整合素 beta 3 信号传导抑制血管生成
DOI：
10.1038/s41598-017-09568-5
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发表时间：
2017-08-25
影响因子：
4.6
通讯作者：
Li W
中科院分区：
文献类型：
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作者：
Cai Z;Dong L;Song C;Zhang Y;Zhu C;Zhang Y;Ling Q;Hoffmann PR;Li J;Huang Z;Li W
靶向血管生成已经成为一种很有前途的癌症治疗策略。甲基硒酸（MSA）是动物细胞中硒（Se）的代谢物，在超过硒营养需求水平时表现出抗氧化和抗癌活性。然而，尚不清楚MSA是否通过影响硒营养水平下的血管生成来发挥其预防癌症的作用。在这里，我们证明MSA在2µM时抑制血管生成，这落在中等硒营养状态的范围内。我们发现2µM的MSA处理增加了细胞粘附，同时抑制HUVECs的细胞迁移和试管形成。此外，MSA能有效抑制小鼠主动脉环的萌发和鸡胚绒毛膜尿囊膜新生血管的生成。我们还发现MSA在mRNA和蛋白水平上下调整合素β3，并破坏整合素β3在细胞表面的聚集。此外，结果显示MSA抑制AKT、i - κ b α和NFκB的磷酸化。综上所述，我们的研究结果表明，外源性MSA抑制营养硒水平下的血管生成不仅通过下调整合素β3的表达，还通过破坏整合素β3的聚集，从而进一步抑制AKT、i - κ b α、nf - κ b的磷酸化。这些发现为MSA调节血管生成的功能提供了新的机制见解，并表明MSA可能是临床抗肿瘤治疗的潜在候选或辅助药物。
Targeting angiogenesis has emerged as a promising strategy for cancer treatment. Methylseleninic acid (MSA) is a metabolite of selenium (Se) in animal cells that exhibits anti-oxidative and anti-cancer activities at levels exceeding Se nutritional requirements. However, it remains unclear whether MSA exerts its effects on cancer prevention by influencing angiogenesis within Se nutritional levels. Herein, we demonstrate that MSA inhibited angiogenesis at 2 µM, which falls in the range of moderate Se nutritional status. We found that MSA treatments at 2 µM increased cell adherence, while inhibiting cell migration and tube formation of HUVECs in vitro. Moreover, MSA effectively inhibited the sprouts of mouse aortic rings and neoangiogenesis in chick embryo chorioallantoic membrane. We also found that MSA down-regulated integrin β3 at the levels of mRNA and protein, and disrupted clustering of integrin β3 on the cell surface. Additionally, results showed that MSA inhibited the phosphorylation of AKT, IκBα, and NFκB. Overall, our results suggest that exogenous MSA inhibited angiogenesis at nutritional Se levels not only by down-regulating the expression of integrin β3 but also by disorganizing the clustering of integrin β3, which further inhibited the phosphorylation involving AKT, IκBα, NFκB. These findings provide novel mechanistic insight into the function of MSA for regulating angiogenesis and suggest that MSA could be a potential candidate or adjuvant for anti-tumor therapy in clinical settings.