Folic acid inhibits endothelial cell proliferation through activating the cSrc/ERK 2/NF-jB/p53 pathway mediated by folic acid receptor

Shyr Yi Lin, Woan Ruoh Lee, Yi Fan Su, Sung Po Hsu, Hsu Chen Lin, Pei Yin Ho, Tien Chi Hou, Yu Pei Chou, Chun Ting Kuo, Wen Sen Lee

研究成果: 雜誌貢獻文章同行評審

32 引文 斯高帕斯(Scopus)

摘要

Folate is important for normal cell division. Folate deficiency has been implicated in various diseases, including atherosclerosis, neural tube defects, and cancer. However, the effect of folate on angiogenesis was unclear. The aim of this study was to investigate the anti-angiogenic action of folic acid (FA). FA (0-10 lmol/L) concentrationdependently decreased DNA synthesis and proliferation in cultured human umbilical venous endothelial cells (HUVEC). Western blot analyses demonstrated that the levels of p21, p27 and p53 protein in HUVEC were increased by FA. The FA-inhibited [3H]thymidine incorporation was completely blocked when the expressions of p21 and p27 were knocked-down together. Knock-down of p53 prevented the FA-induced increases in p21 and p27 protein level. The levels of phosphorylated Src (p-Src) and p-Src- FA receptor (FR) complex in HUVEC were increased by FA. Knock-down of FR reduced the FA-induced increases of p-Src and p53. The FA-induced increases of p21, p27 and p53 protein levels were abolished when cSrc was knocked-down. FA also increased NF-jB nuclear translocation and binding onto the p53 promoter. The FA-induced up-regulation of the p53 promoter activity was prevented by knocked-down of ERK. Matrigel angiogenesis assay in mice demonstrate the anti-angiogenic effect of FA in vivo. In conclusion, our data indicate that FA bound to FR in HUVEC, subsequently activated the cSrc/ERK 2/NF-jB/ p53 signaling pathway, which in turn up-regulated the expression of p21 and p27, and finally resulted in cell cycle arrest at the G0/G1 phase. In the present study, we uncover a completely novel role of FA for anti-angiogenesis.
原文英語
頁(從 - 到)671-683
頁數13
期刊Angiogenesis
15
發行號4
DOIs
出版狀態已發佈 - 2012

ASJC Scopus subject areas

  • Cancer Research
  • Physiology
  • Clinical Biochemistry

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