Methylseleninic Acid Provided at Nutritional Selenium Levels Inhibits Angiogenesis by Down-regulating Integrin β3 Signaling

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 mu M, which falls in the range of moderate Se nutritional status. We found that MSA treatments at 2 mu M 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 beta 3 at the levels of mRNA and protein, and disrupted clustering of integrin beta 3 on the cell surface. Additionally, results showed that MSA inhibited the phosphorylation of AKT, I kappa B alpha, and NF kappa B. Overall, our results suggest that exogenous MSA inhibited angiogenesis at nutritional Se levels not only by down-regulating the expression of integrin beta 3 but also by disorganizing the clustering of integrin beta 3, which further inhibited the phosphorylation involving AKT, I kappa B alpha, NF kappa B. 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.