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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• 作者：Shyr-Yi Lin (1) (2)
  Woan-Ruoh Lee (3) (4) (5)
  Yi-Fan Su (6)
  Sung-Po Hsu (5)
  Hsu-Chen Lin (7)
  Pei-Yin Ho (6)
  Tien-Chi Hou (8)
  Yu-Pei Chou (5)
  Chun-Ting Kuo (5)
  Wen-Sen Lee (10) (5) (9)
  
• 关键词：Angiogenesis ; Endothelium ; Folic acid receptor ; Cell proliferation ; Signaling pathway
• 刊名：Angiogenesis
• 出版年：2012
• 出版时间：December 2012
• 年：2012
• 卷：15
• 期：4
• 页码：671-683
• 全文大小：870KB
• 参考文献：1. Kim YI (2007) Folate and colorectal cancer: an evidence-based critical review. Mol Nutr Food Res 51:267-92 CrossRef
  2. Camilo E, Zimmerman J, Mason JB, Golner B, Russell R, Selhub J, Rosenberg IH (1996) Folate synthesized by bacteria in the human upper small intestine is assimilated by the host. Gastroenterology 110:991-98 CrossRef
  3. Kim YI (2004) Will mandatory folic acid fortification prevent or promote cancer? Am J Clin Nutr 80:1123-128
  4. Choi SW, Mason JB (2002) Folate status: effects on pathways of colorectal carcinogenesis. J Nutr 132(8 suppl):2413S-418S
  5. Kim YI (1999) Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 10:66-8 CrossRef
  6. Yu CH, Wu J, Su YF, Ho PY, Liang YC, Sheu MT, Lee WS (2004) Anti-proliferation effect of 3-amino-2-imino-3,4-dihydro-2H-1,3-benzothiazin-4-one (BJ-601) in human vascular endothelial cells: G0/G1 p21-associated cell cycle arrest. Biochem Pharmacol 67:1907-910 CrossRef
  7. Folkman J (1995) Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med 333:1757-763 CrossRef
  8. Lee WS, Harder JA, Yoshizumi M, Lee ME, Haber E (1997) Progesterone inhibits arterial smooth muscle cell proliferation. Nat Med 3:1005-008 CrossRef
  9. Hsu SP, Chen TH, Chou YP, Chen LC, Kuo CT, Lee TS, Lin JJ, Chang NC, Lee WS (2011) Extra-nuclear activation of progesterone receptor in regulating arterial smooth muscle cell migration. Atherosclerosis 217:83-9 CrossRef
  10. Hsu SP, Ho PY, Juan SH, Liang YC, Lee WS (2008) Progesterone inhibits human endothelial cell proliferation through a p53-dependent pathway. Cell Mol Life Sci 65(23):3839-850 CrossRef
  11. Ho PY, Liang YC, Ho YS, Chen CT, Lee WS (2004) Inhibition of human vascular endothelial cells proliferation by terbinafine. Int J Cancer 111:51-9 CrossRef
  12. Hsu SP, Lee W (2011) Progesterone receptor activation of extra-nuclear signaling pathways in regulating p53 expression in vascular endothelial cells. Mol Endocrinol 25:421-32 CrossRef
  13. Ho PY, Hsu SP, Liang YC, Kuo ML, Ho YS, Lee WS (2008) Inhibition of the ERK phosphorylation plays a role in terbinafine-induced p21 upregulation and DNA synthesis inhibition in human vascular endothelial cells. Toxicol Appl Pharma 229:86-3 CrossRef
  14. Shupnik MA (2004) Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation. Oncogene 23:7979-989 CrossRef
  15. Mitra G, Weber M, Stacey D (1993) Multiple pathways for activation of MAP kinases. Cell Mol Biol Res 39:517-23
  16. Troppmair J, Bruder JT, Munoz H, Lloyd PA, Kyriakis J, Banerjee P, Avruch J, Rapp UR (1994) Mitogen-activated protein kinase/extracellular signal-regulated protein kinase activation by oncogenes, serum, and 12-O-tetradecanoylphorbol-13-acetate requires Raf and is necessary for transformation. J Biol Chem 269:7030-035
  17. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75:805-16 CrossRef
  18. Toyoshima H, Hunter T (1994) p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78:67-4 CrossRef
  19. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366:701-04 CrossRef
  20. Harper JW, Elledge SJ, Keyomarsi K, Dynlacht B, Tsai LH, Zhang P, Dobrowolski S, Bai C, Connell-Crowley L, Swindell E (1995) Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell 6:387-00
  21. Chen J, Jackson PK, Kirschner MW, Dutta A (1995) Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA. Nature 374:386-88 CrossRef
  22. Lin J, Reichner C, Wu X, Levine AJ (1996) Analysis of wild-type and mutant p21WAF-1 gene activities. Mol Cell Biol 16:1786-793
  23. el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75:817-25 CrossRef
  24. el-Deiry WS, Harper JW, O’Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, Wiman KG, Mercer WE, Kastan MB, Kurt WK, Elledge SJ, Kinzler KW, Vogelstein B (1994) WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 54:1169-174
  25. He G, Siddik ZH, Huang Z, Wang R, Koomen J, Kobavashi R, Khokhar AR, Kuang J (2005) Induction of p21 by p53 following DNA damage inhibits both Cdk4 and Cdk2 activities. Oncogene 24:2929-943 CrossRef
  26. Igata M, Motoshima H, Tsuruzoe K, Kojima K, Matsumura T, Kondo T, Taquchi T, Nakamaru K, Yano M, Kukidome D, Matsumoto K, Tovonaqa T, Asano T, Nishikawa T, Araki E (2005) Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression. Circ Res 97:837-44 CrossRef
  27. Barber RC, Lammer EJ, Shaw GM, Greer KA, Finnell R (1999) The role of folate transport and metabolism in neural tube defect risk. Mol Genet Metab 66:1- CrossRef
  28. Kamen BA, Wang MT, Streckfuss AJ, Peryea X, Anderson RG (1988) Delivery of folates to the cytoplasm of MA104 cells is mediated by a surface membrane receptor that recycles. J Biol Chem 263:13602-3609
  29. Page ST, Owen WC, Price K, Elwood PC (1993) Expression of the human placental folate receptor transcript is regulated in human tissues. Organization and full nucleotide sequence of the gene. J Mol Biol 229:1175-183 CrossRef
  
• 作者单位：Shyr-Yi Lin (1) (2)
  Woan-Ruoh Lee (3) (4) (5)
  Yi-Fan Su (6)
  Sung-Po Hsu (5)
  Hsu-Chen Lin (7)
  Pei-Yin Ho (6)
  Tien-Chi Hou (8)
  Yu-Pei Chou (5)
  Chun-Ting Kuo (5)
  Wen-Sen Lee (10) (5) (9)
  
  1. Department of Primary Care Medicine, Taipei Medical University Hospital, Taipei, Taiwan
  2. Department of General Medicine, School of Medicine, Medical College, Taipei Medical University, Taipei, Taiwan
  3. Department of Dermatology, School of Medicine, Medical College, Taipei Medical University, Taipei, Taiwan
  4. Department of Dermatology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan
  5. Graduate Institute of Medical Sciences, School of Medicine, Medical College, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 110, Taiwan
  6. Graduate Institute of Cellular and Molecular Biology, School of Medicine, Medical College, Taipei Medical University, Taipei, Taiwan
  7. Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
  8. Department of Medicine, School of Medicine, Medical College, Taipei Medical University, Taipei, Taiwan
  10. Cancer Research Center, Taipei Medical University Hospital, Taipei, Taiwan
  9. Department of Physiology, School of Medicine, Medical College, Taipei Medical University, Taipei, Taiwan
  
• ISSN：1573-7209

文摘

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 (0-0?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.