Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Genistein Suppresses TPA-Induced Matrix Metalloproteinases Activity and Cell Invasion in Human Breast Adenocarcinoma Cells

인체 유방암세포에서 TPA에 의해 유도된 matrix metalloproteinases 활성 및 침윤성 증대에 미치는 genistein의 영향

  • Choi, Yung-Hyun (Department of Biochemistry, College of Oriental Medicine, Department of Biomaterial Control (BK21 program), Anti-Aging Research Center & Blue-Bio Industry RIC, Dongeui University) ;
  • Kim, Sung-Ok (Department of Herbal Pharmacology of Oriental Medicine, College of Oriental Medicine & R&D Team for the New Drug of Oriental Medicine (BK21), Daegu Hanny University)
  • 최영현 (동의대학교 한의과대학 생화학교실, 대학원 바이오물질제어학과, 항노화연구소 및 블루바이오소재개발센터) ;
  • 김성옥 (대구한의대학교 본초약리학교실 및 BK21 한방신약개발연구팀)
  • Received : 2012.04.30
  • Accepted : 2012.07.19
  • Published : 2012.07.30
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Abstract

Genistein, a predominant isoflavone, has been shown to inhibit the growth of various cancer cells in vitro and in vivo without toxicity to normal cells. In the present study, we investigated the effects of genistein on the activity and the expression of matrix metalloproteinases (MMPs) in MCF-7 and MDA-MB-231 human breast adenocarcinoma cells. Our findings showed that MMP-9 and -2 activation was significantly increased in response to 12-O-tetradecanoyl phorbol-13-acetate (TPA). However, the increased activities of MMP-9 and -2 in TPA-treated cells were concentration-dependently inhibited by treatment with genistein, and this was also correlated with a decrease in the expression of their mRNA and proteins. In addition, a matrigel invasion assay showed that genistein reduced TPA-induced invasion of MCF-7 and MDA-MB-231 cells. Although further in vivo studies are needed, these results suggest that genistein treatment may inhibit tumor cell invasion and, therefore, act as a dietary source to decrease the risk of cancer metastasis.

Genistein은 대두 및 그들의 부산물에 풍부하게 존재하는 isoflavone의 일종으로 정상세포에서는 독성을 나타내지 않는 범위에서 다양한 in vitro 및 in vivo 모델에서 암세포의 증식을 효과적으로 억제할 수 있는 천연물로 알려져 있다. 본 연구에서는 MCF-7 및MDA-MB-231 유방암세포에서 matrix metalloproteinases (MMPs)의 활성 및 발현과 침윤성에 미치는 genistein의 영향을 조사하였다. 본 연구의 결과에 의하면 genistein은 12-O-tetradecanoyl phorbol-13-acetate (TPA) 처리에 의하여 활성화된 MMP-2 및 -9의 활성을 유의적으로 차단하였으며, 이는 전사 및 번역 수준에서 MMP-2 및 -9의 발현 억제와 연관성이 있었다. 또한 matrigel invasion assay를 통하여 genistein은 두 유방암세포의 침윤성을 완벽하게 차단하였음을 관찰하였으며, 이러한 효과는 genistein의 세포독성 효과에 의한 것이 아니었음을 알 수 있었다. 비록 in vivo 동물 실험을 통한 부가적인 연구의 필요성이 있으나, 본 연구의 결과는 genistein이 암의 전이를 억제할 수 있는 효과적인 식이 소재임을 보여주는 것이다.

Keywords

References

  1. Adlercruetz, C. H., Goldin, B. R., Gorbach, S. L., Hockerstedt, K. A. V., Watanabe, S., Hamalainen, E., Markkanen, M. H., Makela, T. H., Wahala, K. T., Hase, T. A. and Fotsis, T. 1996. Soybean phytoestrogen intake and cancer risk. J. Nutr. 125, 757S-770S.
  2. Back, M., Ketelhuth, D. F. and Agewall, S. 2010. Matrix metalloproteinases in atherothrombosis. Prog. Cardiovasc. Dis. 52, 410-428. https://doi.org/10.1016/j.pcad.2009.12.002
  3. Barnes, S. 1995. Effect of genistein on in vitro and in vivo models of cancer. J. Nutr. 125, 777S-783S.
  4. Brooks, S. A., Lomax-Browne, H. J., Carter, T. M., Kinch, C. E. and Hall, D. M. 2010. Molecular interactions in cancer cell metastasis. Acta. Histochem. 112, 3-25. https://doi.org/10.1016/j.acthis.2008.11.022
  5. Brownson, D. M., Azios, N. G., Fuqua, B. K., Dharmawardhane, S. F. and Mabry, T. J. 2002. Flavonoid effects relevant to cancer. J. Nutr. 132, 3482S-3489S.
  6. Chernov, A. V. and Strongin, A. Y. 2011. Epigenetic regulation of matrix metalloproteinases and their collagen substrates in cancer. Biomol. Concepts 2, 135-147.
  7. Chetty, C., Rao, J. S. and Lakka, S. S. 2011. Matrix metalloproteinase pharmacogenomics in non-small-cell lung carcinoma. Pharmacogenomics 12, 535-546. https://doi.org/10.2217/pgs.10.207
  8. Choi, Y. H., Lee, W. H., Park, K. Y, and Zhang, L. 2000. p53-independent induction of p21 (WAF1/CIP1), reduction of cyclin B1 and G2/M arrest by the isoflavone genistein in human prostate carcinoma cells. Jpn. J. Cancer Res. 91, 164-173. https://doi.org/10.1111/j.1349-7006.2000.tb00928.x
  9. Choi, Y. H., Zhang, L., Lee, W. H. and Park, K. Y. 1998. Genistein-induced G2/M arrest is associated with the inhibition of cyclin B1 and the induction of p21 in human breast carcinoma cells. Int. J. Oncol. 13, 391-396.
  10. Curry, T. E. Jr. and Osteen, K. G. 2001. Cyclic changes in the matrix metalloproteinase system in the ovary and uterus. Biol. Reprod. 64, 1285-1296. https://doi.org/10.1095/biolreprod64.5.1285
  11. Farina, H. G., Pomies, M., Alonso, D. F. and Gomez, D. E. 2006. Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer. Oncol. Rep. 16, 885-891.
  12. Gruber, H. E., Ingram, J. A., Hoelscher, G. L., Zinchenko, N., Norton, H. J. and Hanley, E. N. Jr. 2009. Matrix metalloproteinase 28, a novel matrix metalloproteinase, is constitutively expressed in human intervertebral disc tissue and is present in matrix of more degenerated discs. Arthritis Res. Ther. 11, R184. https://doi.org/10.1186/ar2876
  13. Hadler-Olsen, E., Fadnes, B., Sylte, I., Uhlin-Hansen, L. and Winberg, J. O. 2011. Regulation of matrix metalloproteinase activity in health and disease. FEBS J. 278, 28-45. https://doi.org/10.1111/j.1742-4658.2010.07920.x
  14. Huang, Q., Shen, H. M. and Ong, C. N. 2004. Inhibitory effect of emodin on tumor invasion through suppression of activator protein-1 and nuclear factor-kappaB. Biochem. Pharmacol. 68, 361-371. https://doi.org/10.1016/j.bcp.2004.03.032
  15. Huang, X., Chen, S., Xu, L., Liu, Y., Deb, D. K., Platanias, L. C. and Bergan, R. C. 2005. Genistein inhibits p38 map kinase activation, matrix metalloproteinase type 2, and cell invasion in human prostate epithelial cells. Cancer Res. 65, 3470-3478.
  16. Ismail, I. A., Kang, K. S., Lee, H. A., Kim, J. W. and Sohn, Y. K. 2007. Genistein-induced neuronal apoptosis and G2/M cell cycle arrest is associated with MDC1 up-regulation and PLK1 down-regulation. Eur. J. Pharmacol. 575, 12-20. https://doi.org/10.1016/j.ejphar.2007.07.039
  17. Jiang, Y., Goldberg, I. D. and Shi, Y. E. 2002. Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene 21, 2245-2252. https://doi.org/10.1038/sj.onc.1205291
  18. Jin, C. Y., Park, C., Cheong, J., Choi, B. T., Lee, T. H., Lee, J. D., Lee, W. H., Kim, G. Y., Ryu, C. H. and Choi, Y. H. 2007. Genistein sensitizes TRAIL-resistant human gastric adenocarcinoma AGS cells through activation of caspase-3. Cancer Lett. 257, 56-64. https://doi.org/10.1016/j.canlet.2007.06.019
  19. Jin, C. Y., Park, C., Kim, G. Y., Lee, S. J., Kim, W. J. and Choi, Y. H. 2009. Genistein enhances TRAIL-induced apoptosis through inhibition of p38 MAPK signaling in human hepatocellular carcinoma Hep3B cells. Chem. Biol. Interact. 180, 143-150. https://doi.org/10.1016/j.cbi.2009.03.020
  20. Jin, C. Y., Park, C., Moon, S. K., Kim, G. Y., Kwon, T. K., Lee, S. J., Kim, W. J. and Choi, Y. H. 2009. Genistein sensitizes human hepatocellular carcinoma cells to TRAIL-mediated apoptosis by enhancing Bid cleavage. Anticancer Drugs 20, 713-722. https://doi.org/10.1097/CAD.0b013e32832e8998
  21. Kousidou, O. C., Mitropoulou, T. N., Roussidis, A. E., Kletsas, D., Theocharis, A. D. and Karamanos, N. K. 2005. Genistein suppresses the invasive potential of human breast cancer cells through transcriptional regulation of metalloproteinases and their tissue inhibitors. Int. J. Oncol. 26, 1101-1109.
  22. Kupai, K., Szucs, G., Cseh, S., Hajdu, I., Csonka, C., Csont, T. and Ferdinandy, P. 2010. Matrix metalloproteinase activity assays: Importance of zymography. J. Pharmacol. Toxicol. Methods 61, 205-209. https://doi.org/10.1016/j.vascn.2010.02.011
  23. Liotta, L. A., Steeg, P. S. and Stetler-Stevenson, W. G. 1991. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64, 327-336. https://doi.org/10.1016/0092-8674(91)90642-C
  24. Lukaszewicz-Zając, M., Mroczko, B. and Szmitkowski, M. 2011. Gastric cancer - The role of matrix metalloproteinases in tumor progression. Clin. Chim. Acta 412, 1725-1730. https://doi.org/10.1016/j.cca.2011.06.003
  25. Mignatti, P. and Rifkin, D. B. 1993. Biology and biochemistry of proteinases in tumor invasion. Physiol. Rev. 73, 161-95.
  26. Ouyang, G., Yao, L., Ruan, K., Song, G., Mao, Y. and Bao, S. 2009. Genistein induces G2/M cell cycle arrest and apoptosis of human ovarian cancer cells via activation of DNA damage checkpoint pathways. Cell Biol. Int. 33, 1237-1244. https://doi.org/10.1016/j.cellbi.2009.08.011
  27. Phromnoi, K., Yodkeeree, S., Anuchapreeda, S. and Limtrakul, P. 2009. Inhibition of MMP-3 activity and invasion of the MDA-MB-231 human invasive breast carcinoma cell line by bioflavonoids. Acta. Pharmacol. Sin. 30, 1169-1176. https://doi.org/10.1038/aps.2009.107
  28. Puli, S., Lai, J. C. and Bhushan, A. 2006. Inhibition of matrix degrading enzymes and invasion in human glioblastoma (U87MG) cells by isoflavones. J. Neurooncol. 79, 135-142 https://doi.org/10.1007/s11060-006-9126-0
  29. Rowe, R. G. and Weiss, S. J. 2009. Navigating ECM barriers at the invasive front: the cancer cell-stroma interface. Annu. Rev. Cell Dev. Biol. 25, 567-595. https://doi.org/10.1146/annurev.cellbio.24.110707.175315
  30. Valachovicova, T., Slivova, V., Bergman, H., Shuherk, J. and Sliva, D. 2004. Soy isoflavones suppress invasiveness of breast cancer cells by the inhibition of NF-jB/AP-1-dependent and -independent pathways. Int. J. Oncol. 25, 1389-1395.
  31. Visse, R. and Nagase, H. 2003. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 92, 827-839. https://doi.org/10.1161/01.RES.0000070112.80711.3D
  32. Wang, X., Li, K. F., Adams, E. and Van Schepdael, A. 2011. Matrix metalloproteinase inhibitors: a review on bioanalytical methods, pharmacokinetics and metabolism. Curr. Drug Metab. 12, 395-410. https://doi.org/10.2174/138920011795202901
  33. Zhao, R., Xiang, N., Domann, F. E. and Zhong, W. 2009. Effects of selenite and genistein on G2/M cell cycle arrest and apoptosis in human prostate cancer cells. Nutr. Cancer 61, 397-407. https://doi.org/10.1080/01635580802582751

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