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

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Abstract

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 μmol/L) concentration-dependently 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-κB 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-κB/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.

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Acknowledgments

This work was supported by research grants from NSC96-2320-B-038-023, NSC 97-2320-B-038 -033 -MY3, 98TMU-SHH-03-3, and 99TMU-SHH-02-1 to Dr. Lee; NSC-96-2317-B-038-001 to Dr. Lin.

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Authors and Affiliations

  1. Department of Primary Care Medicine, Taipei Medical University Hospital, Taipei, Taiwan

    Shyr-Yi Lin

  2. Department of General Medicine, School of Medicine, Medical College, Taipei Medical University, Taipei, Taiwan

    Shyr-Yi Lin

  3. Department of Dermatology, School of Medicine, Medical College, Taipei Medical University, Taipei, Taiwan

    Woan-Ruoh Lee

  4. Department of Dermatology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan

    Woan-Ruoh Lee

  5. Graduate Institute of Medical Sciences, School of Medicine, Medical College, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 110, Taiwan

    Woan-Ruoh Lee, Sung-Po Hsu, Yu-Pei Chou, Chun-Ting Kuo & Wen-Sen Lee

  6. Graduate Institute of Cellular and Molecular Biology, School of Medicine, Medical College, Taipei Medical University, Taipei, Taiwan

    Yi-Fan Su & Pei-Yin Ho

  7. Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Hsu-Chen Lin

  8. Department of Medicine, School of Medicine, Medical College, Taipei Medical University, Taipei, Taiwan

    Tien-Chi Hou

  9. Department of Physiology, School of Medicine, Medical College, Taipei Medical University, Taipei, Taiwan

    Wen-Sen Lee

  10. Cancer Research Center, Taipei Medical University Hospital, Taipei, Taiwan

    Wen-Sen Lee

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  1. Shyr-Yi Lin
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  2. Woan-Ruoh Lee
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  10. Wen-Sen Lee
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Correspondence to Wen-Sen Lee.

Additional information

Shyr-Yi Lin and Woan-Ruoh Lee contributed equally to this study.

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Lin, SY., Lee, WR., Su, YF. et al. Folic acid inhibits endothelial cell proliferation through activating the cSrc/ERK 2/NF-κB/p53 pathway mediated by folic acid receptor. Angiogenesis 15, 671–683 (2012). https://doi.org/10.1007/s10456-012-9289-6

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  • DOI: https://doi.org/10.1007/s10456-012-9289-6

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