한국식품과학회지 (Korean Journal of Food Science and Technology)

한국식품과학회 (Korean Society of Food Science and Technology)
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혈관내피세포에서 꽃송이버섯(Sparassis crispa) 소수성 추출물의 항혈관신생 활성

Antiangiogenic activity of non-aqueous fraction from Sparassis crispa extract in human umbilical vein endothelial cells

  • 한장미 (선문대학교 제약생명공학과) ;
  • 공소연 (선문대학교 제약생명공학과) ;
  • 송재경 (선문대학교 제약생명공학과) ;
  • 강예재 (선문대학교 수산생명의학과) ;
  • 정혜진 (선문대학교 제약생명공학과)
  • Han, Jang Mi (Department of Pharmaceutical Engineering & Biotechnology, Sun Moon University) ;
  • Gong, So Youn (Department of Pharmaceutical Engineering & Biotechnology, Sun Moon University) ;
  • Sohng, Jae Kyung (Department of Pharmaceutical Engineering & Biotechnology, Sun Moon University) ;
  • Kang, Yue Jai (Department of Aquatic Life and Medical Sciences, Sun Moon University) ;
  • Jung, Hye Jin (Department of Pharmaceutical Engineering & Biotechnology, Sun Moon University)
  • 투고 : 2019.01.01
  • 심사 : 2019.02.08
  • 발행 : 2019.04.30
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초록

본 연구에서는 꽃송이버섯 소수성 추출물(SCF4)의 항혈관신생활성을 혈관내피세포인 HUVECs을 사용하여 확인하였다. 그 결과, SCF4는 세포 독성을 나타내지 않는 $5-25{\mu}g/mL$의 농도에서 VEGF에 의해 유도된 혈관내피세포 증식을 유의적으로 감소시켰을 뿐만 아니라, 혈관내피세포 침윤성과 관 형성 능력을 농도의 존적으로 감소시켜 in vitro 혈관신생을 효과적으로 저해함을 확인하였다. 또한, SCF4는 독성을 나타내지 않고 CAM의 혈관신생을 저해함으로써, in vivo 혈관신생을 효과적으로 저해함을 확인하였다. 마지막으로 SCF4가 혈관신생을 유도하는 주요 신호전달 경로인 VEGFR2, AKT 및 ERK1/2의 전체 단백질 발현 수준의 변화없이 인산화를 저해함을 확인하였다. 따라서, 본 연구는 꽃송이버섯 소수성 추출물이 혈관신생 저해활성을 나타내고 이러한 현상은 VEGFR2 신호전달경로의 억제를 통해 진행됨을 입증하여, 혈관신생 관련 질환 예방 및 치료를 위한 천연물 소재로서의 적용 가능성을 새롭게 제시하였다.

Sparassis crispa is an edible mushroom that is distributed in Korea, Japan, Europe, and North America. It exerts various biological activities such as immunopotentiation, anti-diabetic, anti-cancer, and anti-inflammatory effects. Recently, we separated the health functional non-aqueous fraction from the chloroform extract of S. crispa (SCF4). In this study, we evaluated the antiangiogenic activity of SCF4 in human umbilical vein endothelial cells (HUVECs). SCF4 effectively inhibited vascular endothelial growth factor (VEGF)-induced cell growth at concentrations ($5-25{\mu}g/mL$) showing no cytotoxic effects. SCF4 inhibited VEGF-induced invasiveness and tube formation ability, which are in vitro angiogenic features of HUVECs, in a dose-dependent manner. In addition, SCF4 markedly suppressed in vivo angiogenesis of chorioallantoic membrane from growing chick embryos without cytotoxicity. Furthermore, SCF4 downregulated the phosphorylation of VEGFR2, AKT, and ERK1/2, which are major angiogenic signal mediators. These results suggest that SCF4 inhibited angiogenesis by suppressing the VEGFR2 signaling pathways without cytotoxicity.

키워드

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Fig. 1. The antiproliferative activity of SCF4 on HUVECs.

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Fig. 2. The effect of SCF4 on angiogenesis in vitro.

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Fig. 3. The effect of SCF4 on angiogenesis in vivo.

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Fig. 4. The effect of SCF4 on VEGFR2-dependent signal transduction in HUVECs.

참고문헌

  1. Avramis IA, Kwock R, Avramis VI. Taxotere and vincristine inhibit the secretion of the angiogenesis inducing vascular endothelial growth factor (VEGF) by wild-type and drug-resistant human leukemia T-cell lines. Anticancer Res. 21: 2281-2286 (2001)
  2. Carmeliet P. Angiogenesis in life, disease and medicine. Nature 438: 932-936 (2005) https://doi.org/10.1038/nature04478
  3. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 407: 249-257 (2000) https://doi.org/10.1038/35025220
  4. Clements MK, Jones CB, Cumming M, Daoud SS. Antiangiogenic potential of camptothecin and topotecan. Cancer Chemoth. Pharm. 44: 411-416 (1999) https://doi.org/10.1007/s002800050997
  5. Coultas L, Chawengsaksophak K, Rossant J. Endothelial cells and VEGF in vascular development. Nature 438: 937-945 (2005) https://doi.org/10.1038/nature04479
  6. de Falco S. Antiangiogenesis therapy: an update after the first decade. Korean J. Intern. Med. 29: 1-11 (2014) https://doi.org/10.3904/kjim.2014.29.1.1
  7. Du J, Xu R, Hu Z, Tian Y, Zhu Y, Gu L, Zhou L. PI3K and ERKinduced Rac1 activation mediates hypoxia-induced HIF-1${\alpha}$ expression in MCF-7 breast cancer cells. PLoS One 6: e25213 (2011) https://doi.org/10.1371/journal.pone.0025213
  8. Fan TP, Yeh JC, Leung KW, Yue PY, Wong RN. Angiogenesis: From plants to blood vessels. Trends Pharmacol. Sci. 27: 297-309 (2006) https://doi.org/10.1016/j.tips.2006.04.006
  9. Gerber HP, Mc Murtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J. Biol. Chem. 273: 30336-30343 (1998) https://doi.org/10.1074/jbc.273.46.30336
  10. Han JM, Kwon HJ, Jung HJ. Tricin, 4',5,7-trihydroxy-3',5'-dimethoxyflavone, exhibits potent antiangiogenic activity in vitro. Int. J. Oncol. 49: 1497-1504 (2016) https://doi.org/10.3892/ijo.2016.3645
  11. Han JM, Lee EK, Gong SY, Sohng JK, Kang YJ, Jung HJ. Sparassis crispa exerts anti-inflammatory activity via suppression of TLRmediated NF-${\kappa}$B and MAPK signaling pathways in LPS-induced RAW264.7 macrophage cells. J. Ethnopharmacol. 231: 10-18 (2019) https://doi.org/10.1016/j.jep.2018.11.003
  12. Han JM, Lim HN, Jung HJ. Hovenia dulcis Thunb. and its active compound ampelopsin inhibit angiogenesis through suppression of VEGFR2 signaling and HIF-$1{\alpha}$ expression. Oncol. Rep. 38: 3430-3438 (2017) https://doi.org/10.3892/or.2017.6021
  13. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J. Clin. Oncol. 23: 1011-1027 (2005) https://doi.org/10.1200/JCO.2005.06.081
  14. Hida TH, Kawaminami H, Ishibashi K, Miura NN, Adachi Y, Ohno N. Oral administration of soluble ${\beta}$-glucan preparation from the cauliflower mushroom, Sparassis crispa (Higher Basidiomycetes) modulated cytokine production in mice. Int. J. Med. Mushrooms 15: 525-538 (2013) https://doi.org/10.1615/IntJMedMushr.v15.i6.20
  15. Holmes K, Roberts OL, Thomas AM, Cross MJ. Vascular endothelial growth factor receptor-2: Structure, function, intracellular signalling and therapeutic inhibition. Cell. Signal. 19: 2003-2012 (2007) https://doi.org/10.1016/j.cellsig.2007.05.013
  16. Hong KB, Hong SY, Joung EY, Kim BH, Bae SH, Park Y, Suh HJ. Hypocholesterolemic effects of the cauliflower culinary-medicinal mushroom, Sparassis crispa (Higher Basidiomycetes), in dietinduced hypercholesterolemic rats. Int. J. Med. Mushrooms 17: 965-975 (2015) https://doi.org/10.1615/IntJMedMushrooms.v17.i10.60
  17. Jing Y, Liu LZ, Jiang Y, Zhu Y, Guo NL, Bamett J, Rojanasakul Y, Agani F, Jiang BH. Cadmium increases HIF-1 and VEGF expression through ROS, ERK, and AKT signaling pathways and induces malignant transformation of human bronchial epithelial cells. Toxicol. Sci. 125: 10-19 (2012) https://doi.org/10.1093/toxsci/kfr256
  18. Kim HH, Lee S, Singh TS, Choi JK, Shin TY, Kim SH. Sparassis crispa suppresses mast cell-mediated allergic inflammation: role of calcium, mitogen-activated protein kinase and nuclear factor-Kb. Int. J. Mol. Med. 30: 344-350 (2012) https://doi.org/10.3892/ijmm.2012.1000
  19. Kimura T. Natural products and biological activity of the pharmacologically active cauliflower mushroom Sparassis crispa. Biomed. Res. Int. 2013: 982317 (2013) https://doi.org/10.1155/2013/982317
  20. Ohno N, Miura NN, Nakajima M, Yadomae T. Antitumor 1,3-betaglucan from cultured fruit body of Sparassis crispa. Biol. Pharm. Bull. 23: 866-872 (2000) https://doi.org/10.1248/bpb.23.866
  21. Rajendran P, Rengarajan T, Thangavel J, Nishigaki Y, Sakthisekaran D, Sethi G. The Vascular Endothelium and Human Diseases. Int. J. Biol. Sci. 9: 1057-1069 (2013) https://doi.org/10.7150/ijbs.7502
  22. Shi YH, Wang YX, Bingle L, Gong LH, Heng WJ, Li Y, Fang WG. In vitro study of HIF-1 activation and VEGF release by bFGF in the T47D breast cancer cell line under normotoxic conditions: involvement of PI-3K/Akt and MEK1/ERK pathways. J. Pathol. 205: 530-536 (2005) https://doi.org/10.1002/path.1734
  23. Vincent L, Kermani P, Young LM, Cheng J, Zhang F, Shido K, Lam G, Bompais-Vincent H, Zhu Z, Hicklin DJ, Bohlen P, Chaplin DJ, May C, Rafii S. Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling. J. Clin. Invest. 115: 2992-3006 (2005) https://doi.org/10.1172/JCI24586
  24. Yamamoto K., Kimura T. Orally and topically administered Sparassis crispa (Hanabiratake) improved healing of skin wounds in mice with streptozotocin-induced diabetes. Biosci. Biotechnol. Biochem. 77: 1303-1305 (2013) https://doi.org/10.1271/bbb.121016
  25. Yamamoto K, Kimura T, Sugitachi A, Matsuura N. Anti-angiogenic and anti-metastatic effects of beta-1,3-D-glucan purified from Hanabiratake, Sparassis crispa. Biol. Pharm. Bull. 32: 259-263 (2009) https://doi.org/10.1248/bpb.32.259
  26. Yoshida M, Hida TH, Takeshita K, Tsuboi M, Kanamori M, Akachi N, Miura NN, Adachi Y, Ohno N. Effect of Sasa veitchii extract on immunostimulating activity of ${\beta}$-glucan (SCG) from culinarymedicinal mushroom Sparassis crispa Wulf.:Fr. (higher Basidiomycetes). Int. J. Med. Mushrooms 14: 537-547 (2012) https://doi.org/10.1615/IntJMedMushr.v14.i6.10