Biomolecules & Therapeutics

  • 제19권4호
  • /
  • Pages.411-418
  • /
  • 2011
  • /
  • 1976-9148(pISSN)
  • /
  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
권호 표지
DOI QR코드

DOI QR Code

Ginsenoside Rp1 Inhibits Proliferation and Migration of Human Lung Cancer Cells

  • Hong, Sam-Yeol (Department of Molecular Bioscience, Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University) ;
  • Cho, Jae-Youl (Department of Genetic Engineering, School of Life Science and Biotechnology, Sungkyunkwan University) ;
  • Seo, Dong-Wan (Department of Molecular Bioscience, Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University)
  • 투고 : 2011.06.29
  • 심사 : 2011.08.09
  • 발행 : 2011.10.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Ginsenoside Rp1 (G-Rp1) is a novel ginseng saponin derivative with anti-tumor activity. However, the biochemical and molecular mechanisms of G-Rp1 on anti-tumor activity are not fully understood. In the present study, we report that G-Rp1 inhibits lung cancer cell proliferation, migration and adhesion in p53 wild-type A549 and p53-defi cient H1299 cells. Anti-proliferative activity of G-Rp1 in lung cancer cells is mediated by enhanced nuclear localization of cyclin-dependent kinase inhibitors including $p27^{Kip1}$ and $p21^{WAF1/Cip1}$, and subsequent inhibition of pRb phosphorylation. We also show that these anti-tumor activities of G-Rp1 in both A549 and H1299 cells appear to be mediated by suppression of mitogenic signaling pathways such as ERK, Akt and $p70^{S6K}$. Taken together, these findings suggest further development and evaluation of G-Rp1 for the treatment of lung cancers with mutated p53 as well as wild-type p53.

키워드

참고문헌

  1. Alper, O., Bergmann-Leitner, E. S., Bennett, T. A., Hacker, N. F., Stromberg, K. and Stetler-Stevenson, W. G. (2001) Epidermal growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells. J. Natl. Cancer Inst. 93, 1375-1384. https://doi.org/10.1093/jnci/93.18.1375
  2. Attele, A. S., Wu, J. A. and Yuan, C. S. (1999) Ginseng pharmacology: Multiple constituents and multiple actions. Biochem. Pharmacol. 58, 1685-1693. https://doi.org/10.1016/S0006-2952(99)00212-9
  3. Baek, N. I., Kim, D. S., Lee, Y. H., Park, J. D., Lee, C. B. and Kim, S. I. (1996) Ginsenoside Rh4, a genuine dammarane glycoside from Korean red ginseng. Planta. Med. 62, 86-87. https://doi.org/10.1055/s-2006-957816
  4. Bourboulia, D. and Stetler-Stevenson, W. G. (2010) Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Semin. Cancer Biol. 20, 161-168. https://doi.org/10.1016/j.semcancer.2010.05.002
  5. Cheng, C. C., Yang, S. M., Huang, C. Y., Chen, J. C., Chang, W. M. and Hsu, S. L. (2005) Molecular mechanisms of ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells. Cancer Chemother. Pharmacol. 55, 531-540. https://doi.org/10.1007/s00280-004-0919-6
  6. Cho, Y. R., Kim, S. H., Ko, H. Y., Kim, M. D., Choi, S. W. and Seo, D. W. (2011) Sepiapterin inhibits cell proliferation and migration of ovarian cancer cells via down-regulation of $p70^{S6K}$-dependent VEGFR-2 expression. Oncol. Rep. 26, 861-867.
  7. Choi, S., Kim, H. J., Ko, Y. S., Jeong, S. W., Kim, Y. I., Simonds, W. F., Oh, J. W. and Nah, S. Y. (2001) Gaq/11 coupled to mammalian phospholipase C b3-like enzyme mediates the ginsenoside effect on $Ca^{2+}$-activated Cl- current in the xenopus oocyte. J. Biol. Chem. 276, 48797-48802. https://doi.org/10.1074/jbc.M104346200
  8. Choi, S., Kim, T. W. and Singh, S. (2009) Ginsenoside Rh2-mediated G1 phase cell cycle arrest in human breast cancer cells is caused by $p15^{Ink4B}$ and $p27^{Kip1}$-dependent inhibition of cyclin-dependent kinases. Pharm. Res. 26, 2280-2288. https://doi.org/10.1007/s11095-009-9944-9
  9. Christofori, G. (2006) New signals from the invasive front. Nature. 441, 444-450. https://doi.org/10.1038/nature04872
  10. Fenton, T. R. and Gout, I. T. (2011) Functions and regulation of the 70kDa ribosomal S6 kinases. Int. J. Biochem. Cell Biol. 43, 47-59. https://doi.org/10.1016/j.biocel.2010.09.018
  11. Fuster, J. J., Sanz-Gonzalez, S. M., Moll, U. M. and Andres, V. (2007) Classic and novel roles of p53: prospects for anticancer therapy. Trends Mol. Med. 13, 192-199. https://doi.org/10.1016/j.molmed.2007.03.002
  12. Han, B. H., Park, M. H., Han, Y. N., Woo, L. K., Sankawa, U., Yahara, S. and Tanaka, O. (1982) Degradation of ginseng saponins under mild acidic conditions. Planta Med. 44, 146-149. https://doi.org/10.1055/s-2007-971425
  13. Hanahan, D. and Weinberg, R. A. (2011) Hallmarks of cancer: The next generation. Cell. 144, 646-674. https://doi.org/10.1016/j.cell.2011.02.013
  14. Harbour, J. W., Luo, R. X., Santi, A. D., Postigo, A. A. and Dean, D. C. (1999) Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell. 98, 859-869. https://doi.org/10.1016/S0092-8674(00)81519-6
  15. Jin, Y. H., Yoo, K. J., Lee, Y. H. and Lee, S. K. (2000) Caspase 3-mediated cleavage of $p21^{WAF1/CIP1}$associated with the cyclin A-cyclindependent kinase 2 complex is a prerequisite for apoptosis in SKHEP- 1 cells. J. Biol. Chem. 275, 30256-30263. https://doi.org/10.1074/jbc.M001902200
  16. Kim, B. H. and Cho, J. Y. (2009) Regulatory role of ginsenoside Rp1, a novel ginsenoside derivative, on CD29-mediated cell adhesion. Planta Med. 75, 316-320. https://doi.org/10.1055/s-0028-1112213
  17. Kumar, A., Kumar, M., Panwar, M., Samarth, R. M., Park, T. Y., Park, M. H. and Kimura, H. (2006) Evaluation of chemopreventive action of Ginsenoside Rp1. Biofactors 26, 29-43. https://doi.org/10.1002/biof.5520260104
  18. Kumar, A., Kumar, M., Park, T. Y., Park, M. H., Takemoto, T., Terado, T., Kitano, M. and Kimura, H. (2009) Molecular mechanisms of ginsenoside Rp1-mediated growth arrest and apoptosis. Int. J. Mol. Med. 24, 381-386.
  19. Lee, B. H., Lee, J. H., Lee, S. M., Jeong, S. M., Yoon, I. S., Lee, J. H., Choi, S. H., Pyo, M. K., Rhim, H., Kim, H. C., Jang, C. G., Lee, B. C., Park, C. S. and Nah, S. Y. (2007) Identifi cation of ginsenoside interaction sites in $5-HT_{3A}$ receptors. Neuropharmacology 52, 1139-1150. https://doi.org/10.1016/j.neuropharm.2006.12.001
  20. Lee, K. Y., Park, J. A., Chung, E., Lee, Y. H., Kim, S. and Lee, S. K. (1996) Ginsenoside-Rh2 blocks the cell cycle of SK-HEP-1 cells at the G1/S boundary by selectively inducing the protein expression of $p27^{kip1}$. Cancer Lett. 110, 193-200. https://doi.org/10.1016/S0304-3835(96)04502-8
  21. Lemmon, M. A. and Schlessinger, J. (2010) Cell signaling by receptor tyrosine kinases. Cell. 141, 1117-1134. https://doi.org/10.1016/j.cell.2010.06.011
  22. Leung, K. W., Pon, Y. L., Wong, R. N. S. and Wong, A. S. T. (2006) Ginsenoside-Rg1 induces vascular endothelial growth factor expression through the glucocorticoid receptor-related phosphatidylinositol 3-kinase/Akt and b-catenin/T-cell factor-dependent pathway in human endothelial cells. J. Biol. Chem. 281, 36280-36288. https://doi.org/10.1074/jbc.M606698200
  23. Malumbres, M. and Barbacid, M. (2001) Milestones in cell division : To cycle or not to cycle: a critical decision in cancer. Nat. Rev. Cancer. 1, 222-231. https://doi.org/10.1038/35106065
  24. Park, I. H., Piao, L. Z., Kwon, S. W., Lee, Y. J., Cho, S. Y., Park, M. K. and Park, J. H. (2002) Cytotoxic dammarane glycosides from processed ginseng. Chem. Pharm. Bull. 50, 538-540. https://doi.org/10.1248/cpb.50.538
  25. Park, J. W., Lee, J. C., Ann, S., Seo, D. W., Choi, W. S., Yoo, Y. H., Park, S. K., Choi, J. Y., Um, S. H., Ann, S. H. and Han, J. W. (2011) A fermented ginseng extract, BST204, inhibits proliferation and motility of human colon cancer cells. Biomol. Ther. 19, 211-217. https://doi.org/10.4062/biomolther.2011.19.2.211
  26. Park, T. Y., Park, M. H., Shin, W. C., Rhee, M. H., Seo, D. W., Cho, J. Y. and Kim, H. M. (2008) Anti-metastatic potential of ginsenoside Rp1, a novel ginsenoside derivative. Biol. Pharm. Bull. 31, 1802-1805. https://doi.org/10.1248/bpb.31.1802
  27. Qi, L. W., Wang, C. Z. and Yuan, C. S. (2011) Ginsenosides from American ginseng: Chemical and pharmacological diversity. Phytochemistry. 72, 689-699. https://doi.org/10.1016/j.phytochem.2011.02.012
  28. Sala, F., Mulet, J., Choi, S., Jung, S. Y., Nah, S. Y., Rhim, H., Valor, L. M., Criado, M. and Sala, S. (2002) Effects of ginsenoside Rg2 on human neuronal nicotinic acetylcholine receptors. J. Pharmacol. Exp. Ther. 301, 1052-1059. https://doi.org/10.1124/jpet.301.3.1052
  29. Seo, D. W., Kim, S. H., Eom, S. H., Yoon, H. J., Cho, Y. R., Kim, P. H., Kim, Y. K., Han, J. W., Diaz, T., Wei, B. Y. and Stetler-Stevenson, W. G. (2008) TIMP-2 disrupts FGF-2-induced downstream signaling pathways. Microvasc. Res. 76, 145-151. https://doi.org/10.1016/j.mvr.2008.07.003
  30. Seo, D. W., Li, H., Guedez, L., Wingfi eld, P. T., Diaz, T., Salloum, R., Wei, B. Y. and Stetler-Stevenson, W. G. (2003) TIMP-2 mediated inhibition of angiogenesis: An MMP-independent mechanism. Cell. 114, 171-180. https://doi.org/10.1016/S0092-8674(03)00551-8
  31. Seo, D. W., Li, H., Qu, C. K., Oh, J., Kim, Y. S., Diaz, T., Wei, B., Han, J. W. and Stetler-Stevenson, W. G. (2006) Shp-1 mediates the antiproliferative activity of tissue inhibitor of metalloproteinase-2 in human microvascular endothelial cells. J. Biol. Chem. 281, 3711-3721. https://doi.org/10.1074/jbc.M509932200
  32. Sherr, C. J. and Roberts, J. M. (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501-1512. https://doi.org/10.1101/gad.13.12.1501
  33. Shi, A. W., Wang, X. B., Lu, F. X., Zhu, M. M., Kong, X. Q. and Cao, K. J. (2009) Ginsenoside Rg1 promotes endothelial progenitor cell migration and proliferation. Acta Pharmacol. Sin. 30, 299-306. https://doi.org/10.1038/aps.2009.6
  34. Shibata, S. (2001) Chemistry and cancer preventing activities of ginseng saponins and some related triterpenoid compounds. J. Korean Med. Sci. 16, S28-S37. https://doi.org/10.3346/jkms.2001.16.S.S28
  35. Stetler-Stevenson, W. G., Aznavoorian, S. and Liotta, L. A. (1993) Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu. Rev. Cell Biol. 9, 541-573. https://doi.org/10.1146/annurev.cb.09.110193.002545
  36. Tachikawa, E., Kudo, K., Harada, K., Kashimoto, T., Miyate, Y., Kakizaki, A. and Takahashi, E. (1999) Effects of ginseng saponins on responses induced by various receptor stimuli. Eur. J. Pharmacol. 369, 23-32. https://doi.org/10.1016/S0014-2999(99)00043-6
  37. Wang, W., Rayburn, E. R., Hang, J., Zhao, Y., Wang, H. and Zhang, R. (2009) Anti-lung cancer effects of novel ginsenoside 25-OCH3-PPD. Lung Cancer 65, 306-311. https://doi.org/10.1016/j.lungcan.2008.11.016
  38. Yue, P. Y. K., Wong, D. Y. L., Wu, P. K., Leung, P. Y., Mak, N. K., Yeung, H. W., Liu, L., Cai, Z., Jiang, Z.-H., Fan, T. P. D. and Wong, R. N. S. (2006) The angiosuppressive effects of 20(R)- ginsenoside Rg3. Biochem. Pharmacol. 72, 437-445. https://doi.org/10.1016/j.bcp.2006.04.034
  39. Yun, T. K. (2003) Experimental and epidemiological evidence on nonorgan specifi c cancer preventive effect of Korean ginseng and identifi cation of active compounds. Mutat. Res. 523-524, 63-74. https://doi.org/10.1016/S0027-5107(02)00322-6
  40. Yun, T. K. (2001) Panax ginseng--a non-organ-specifi c cancer preventive? Lancet Oncol. 2, 49-55. https://doi.org/10.1016/S1470-2045(00)00196-0

피인용 문헌

  1. Compound K, a metabolite of ginseng saponin, inhibits colorectal cancer cell growth and induces apoptosis through inhibition of histone deacetylase activity vol.43, pp.6, 2013, https://doi.org/10.3892/ijo.2013.2129
  2. The role of a ginseng saponin metabolite as a DNA methyltransferase inhibitor in colorectal cancer cells vol.43, pp.1, 2013, https://doi.org/10.3892/ijo.2013.1931
  3. A mechanistic study on the anti-cancer activity of ethyl caffeate in human ovarian cancer SKOV-3 cells vol.219, 2014, https://doi.org/10.1016/j.cbi.2014.05.017
  4. The in vitro antitumor activity of Siegesbeckia glabrescens against ovarian cancer through suppression of receptor tyrosine kinase expression and the signaling pathways vol.30, pp.1, 2013, https://doi.org/10.3892/or.2013.2468
  5. Knockdown of integrin α3β1 expression induces proliferation and migration of non-small cell lung cancer cells vol.29, pp.2, 2013, https://doi.org/10.3892/or.2012.2169
  6. Chikusetsusaponin IVa methyl ester induces G1 cell cycle arrest, triggers apoptosis and inhibits migration and invasion in ovarian cancer cells vol.23, pp.13, 2016, https://doi.org/10.1016/j.phymed.2016.09.002