Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Genistein-induced Growth Inhibition was Associated with Inhibition of Cyclooxygenase-2 and Telomerase Activity in Human Cancer Cells.

인체 암세포에서 genistein에 의한 cyclooxygenase-2 및 telomerase의 활성 저하

  • Kim, Jung-Im (Department of Biochemistry, Dongeui University College of Oriental Medicine) ;
  • Kim, Seong-Yun (Department of Biomaterial Control (BK21 program), Dongeui University Graduate School) ;
  • Seo, Min-Jeong (Department of Biotechnology, College of Natural Resources and Life Science and BK21 Center for Silver-Bio Industrialization, Dong-A University) ;
  • Lim, Hak-Seob (Bioinstitute, Millennium Promise Co., LTD) ;
  • Lee, Young-Choon (Department of Biotechnology, College of Natural Resources and Life Science and BK21 Center for Silver-Bio Industrialization, Dong-A University) ;
  • Joo, Woo-Hong (Department of Biology, Changwon National University) ;
  • Choi, Byung-Tae (Department of Anatomy, Graduate School of Oriental Medicine, Pusan National University) ;
  • Jeong, Yong-Kee (Department of Biotechnology, College of Natural Resources and Life Science and BK21 Center for Silver-Bio Industrialization, Dong-A University) ;
  • Choi, Yung-Hyun (Department of Biochemistry, Dongeui University College of Oriental Medicine, Department of Biomaterial Control (BK21 program), Dongeui University Graduate School)
  • 김정임 (동의대학교 한의과대학 생화학교실) ;
  • 김성윤 (동의대학교 대학원 바이오물질제어학과(BK 21 program)) ;
  • 서민정 (동아대학교 생명자원과학대학 생명공학과) ;
  • 임학섭 ((주)천연약속) ;
  • 이영춘 (동아대학교 생명자원과학대학 생명공학과) ;
  • 주우홍 (창원대학교 자연과학대학 생물학과) ;
  • 최병태 (부산대학교 한의학전문대학원 해부학교실) ;
  • 정영기 (동아대학교 생명자원과학대학 생명공학과) ;
  • 최영현 (동의대학교 한의과대학 생화학교실, 동의대학교 대학원 바이오물질제어학과(BK 21 program))
  • Published : 2008.06.30
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Abstract

Genistein, an isoflavone in soybean products, is a potential chemopreventive agent against various types of cancer. There are several studies documenting molecular alterations leading to cell cycle arrest at G2/M phase and induction of apoptosis; however, its mechanism of action and its molecular targets on the prostaglandin $E_2$ ($PGE_2$) production and telomere length regulation in human cancer remain unclear. In this study, we investigated the effect of genistein on the levels of cyclooxygenases (COXs) and telomere regulatory components of several human cancer cell lines (T24, human bladder carcinoma cells; U937, human leukemic cells; AGS, human stomach adenocarcinoma cells and SK-MEL-2, human skin melanoma cells). Genistein treatment resulted in the inhibition of cancer cell proliferation in a concentration-dependent manner. It was found that genistein treatment markedly decreased the levels of COX-2 mRNA and protein expression without significant changes in the expression of COX-1, which was correlated with a decrease in $PGE_2$ synthesis. Genistein treatment also partly inhibited the levels of human telomerase reverse transcriptase (hTERT) as well as human telomerase RNA (hTR) and telomerase-associated protein (TEP)-1, and the activity of telomerase. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of genistein.

본 연구에서는 대두의 대표적인 생리활성 물질인 genistein의 처리에 따른 암세포의 증식억제에서 telomerase 및 COX-2 활성의 변화 연관성을 조사하였다. 이를 위하여 4가지 종류의 암세포주를 사용하였으며, genistein 처리에 의하여 암세포들의 증식억제에서 백혈병 세포인 U937 세포의 감수성이 감장 높게 나타났으며, genistein 처리에 따라 telomere 조절인자들의 발현이 대부분 억제되었으며, telomerase의 활성도 매우 유의적으로 감소되었다. 또한 genistein처리 농도가 증가함에 따라 COX-2의 발현이 전사 및 번역 수준에서 모두 감소되었으며 이에 따른 $PGE_2$의 생성 역시 현저하게 감소되었으나, COX-1의 발현에는 큰 변화가 없었다. 이러한 결과들은 genistein의 항암 활성을 이해하는 귀중한 자료로서 활용될 것으로 생각된다.

Keywords

References

  1. Adlercreutz, H. 1990. Western diet and Western diseases: some hormonal and biochemical mechanisms and associations. Scand. J. Clin. Lab. Invest. 201, 3S-23S
  2. Alhasan, S. A., O. Aranha and F. H. Sarkar. 2001. Genistein elicits pleiotropic molecular effects on head and neck cancer cells. Clin. Cancer Res. 7, 4174-4181
  3. Barnes, S. 1995. Related Effect of genistein on in vitro and in vivo models of cancer. J. Nutr. 125, 777-783
  4. Bises, G., E. Bajna, T. Manhardt, W. Gerdenitsch, E. Kallay and H. S. Cross. 2007. Gender-specific modulation of markers for premalignancy by nutritional soy and calcium in the mouse colon. J. Nutr. 137, 211S-215S https://doi.org/10.1093/jn/137.1.211S
  5. Cerni, C. 2000. Telomeres, telomerase, and myc. An update, Mutat. Res. 462, 31-47
  6. Chinni, S. R., S. A. Alhasan, A. S. Multani, S. Pathak and F. H. Sarkar. 2003. Pleotropic effects of genistein on MCF-7 breast cancer cells. Int. J. Mol. Med. 12, 29-34
  7. Choi, Y. H., W. H. Lee, K. Y. Park and L. Zhang. 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
  8. Choi, Y. H., L. Zhang, W. H. Lee and K. Y. Park. 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
  9. Choi, W. Y., C. Park, K. M. Kim, M. H. Han, Y. H. Choi and W. H. Lee. 2006. Induction of G2/M arrest by genistein in human AGS gastric carcinoma and SK-MEL-2 melanoma cells. Cancer Prev. Res. 11, 311-320
  10. Gescher, A. J., R. A. Sharma and W. P. Steward. 2001. Cancer chemoprevention by dietary constituents: a tale of failure and promise. Lancet Oncol. 2, 371-379 https://doi.org/10.1016/S1470-2045(00)00392-2
  11. Giercksky, K. E. 2001. COX-2 inhibition and prevention of cancer. Best Pract. Res. Clin. Gastroenterol. 15, 821-833 https://doi.org/10.1053/bega.2001.0237
  12. Gu, Y., C. F. Zhu, H. Iwamoto and J. S. Chen. 2005. Genistein inhibits invasive potential of human hepatocellular carcinoma by altering cell cycle, apoptosis, and angiogenesis. World J. Gastroenterol. 11, 6512-6517 https://doi.org/10.3748/wjg.v11.i41.6512
  13. Huang, J., M. Nasr, Y. Kim and H. R. Matthews. 1992. Genistein inhibits protein histidine kinase. J. Biol. Chem. 267, 15511-15515
  14. Hwang, J. T., J. Ha and O. J. Park. 2005. Combination of 5-fluorouracil and genistein induces apoptosis synergistically in chemo-resistant cancer cells through the modulation of AMPK and COX-2 signaling pathways. Biochem. Biophys. Res. Commun. 332, 433-440 https://doi.org/10.1016/j.bbrc.2005.04.143
  15. Ismail, I. A., K. S. Kang, H. A. Lee, J. W. Kim and Y. K. Sohn. 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
  16. Jin, C. Y., C. Park, J. Cheong, B. T. Choi, T. H. Lee, J. D. Lee, W. H. Lee, G. Y. Kim, C. H. Ryu and Y. H. Choi. 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
  17. Kim, E. K., Y. H. Myong, K. S. Song, K. H. Lee, C. H. Rhu and Y. H. Choi. 2006. Induction of G2/M arrest of the cell cycle by genistein in human bladder carcinoma and leukemic cells. J. Life Sci. 16, 589-597 https://doi.org/10.5352/JLS.2006.16.4.589
  18. Kim, J. I., C. Park, B. T. Choi, C. H. Rhu, W. H. Lee and Y. H. Choi. 2006. Induction of apoptosis by genistein through caspase-3 activation in human gastric carcinoma and melanoma cells. Cancer Prev. Res. 11, 225-234
  19. Kyo, S. and M. Inoue. 2002. Complex regulatory mechanisms of telomerase activity in normal and cancer cells: How can we apply them for cancer therapy. Oncogene 21, 688-697, 2002 https://doi.org/10.1038/sj.onc.1205163
  20. Messina, M. and S. Barnes. 1991. The role of soy products in reducing risk of cancer. J. Natl. Cancer Inst. 83, 541-546 https://doi.org/10.1093/jnci/83.8.541
  21. Narayan, S., A. S. Jaiswal, A. S. Multani and S. Pathak. 2001. DNA damage-induced cell cycle checkpoints involve both p53-dependent and -independent pathways: role of telomere repeat binding factor 2. Br. J. Cancer 85, 898-901 https://doi.org/10.1054/bjoc.2001.2002
  22. Ogawara, H., T. Akiyama, J. Ishida, S. Watanabe and K. Suzuki. 1986. A specific inhibitor for tyrosine protein kinase from Pseudomonas. J. Antibiot. (Tokyo) 39, 606-608 https://doi.org/10.7164/antibiotics.39.606
  23. Okura, A., H. Arakawa, H. Oka, T. Yoshinari and Y. Monden. 1988. Effect of genistein on topoisomerase activity and on the growth of [Val 12]Ha-ras-transformed NIH 3T3 cells. Biochem. Biophys. Res. Commun. 157, 183-189 https://doi.org/10.1016/S0006-291X(88)80030-5
  24. Peterson, G. and S. Barnes. 1993. Genistein and biochanin A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation. Prostate 22, 335-345 https://doi.org/10.1002/pros.2990220408
  25. Poole, J. C., L. G. Andrews and T. O. Tollefsbol. 2001. Activity, function, and gene regulation of the catalytic subunit of telomerase (hTERT). Gene 269, 1-12 https://doi.org/10.1016/S0378-1119(01)00440-1
  26. Setchell, K. D. 1998. Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones. Am. J. Clin. Nutr. 68, 1333-1346 https://doi.org/10.1093/ajcn/68.6.1333S
  27. Su, S. J., T. M. Yeh, W. J. Chuang, C. L. Ho, K. L. Chang, H. L. Cheng, H. S. Liu, H. L. Cheng, P. Y. Hsu and N. H. Chow. 2005. The novel targets for anti-angiogenesis of genistein on human cancer cells. Biochem. Pharmacol. 69, 307-318 https://doi.org/10.1016/j.bcp.2004.09.025
  28. Surh, Y. J., K. S. Chun, H. H. Cha, S. S. Han, Y. S. Keum, K. K. Park and S. S. Lee. 2001. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-$_K$B activation. Mutat. Res. 480-481, 243-268 https://doi.org/10.1016/S0027-5107(01)00183-X
  29. Thun, M. J., S. J. Henley and C. Patrono. 2002. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J. Natl. Cancer Inst. 94, 252-266 https://doi.org/10.1093/jnci/94.4.252

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