생명과학회지 (Journal of Life Science)

  • 제18권1호
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  • Pages.96-102
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  • 2008
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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Piceatannol에 의한 인체 혈구암세포의 증식 억제 및 telomerase 활성 저하

Induction of S Phase Arrest of the Cell Cycle by Piceatannol is Associated with Inhibition of Telomerase Activity in Human Leukemic U937 Cells

  • 최영현 (동의대학교 한의과대학 생화학교실 및 대학원 바이오물질제어학과)
  • Choi, Yung-Hyun (Department of Biochemistry, Dongeui University College of Oriental Medicine and Department of Biomaterial Control, Dongeui University Graduate School)
  • 발행 : 2008.01.31
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초록

이상의 연구 결과에 의하면 piceatannol의 처리에 의한 U937 세포의 증식억제는 세포주기 S기 arrest 및 apoptosis 유발과 뚜렷한 연관성이 있었다. 또한 piceatannol은 hTERT 및 TEP-1 유전자의 발현 저하와 연관된 telomerase 활성의 저하 효과도 나타내었으나, COXs의 발현 및 PGE2의 생성에는 큰 변화를 주지 못하였다. 따라서 본 연구의 결과는 암세포에서 높게 발현되는 telomerase 활성 조절제로서 piceatannol의 적용이 가능함을 보여주며, 이는 piceatannol의 항암작용을 이해하는데 매우 유용한 자료라 생각한다.

Piceatannol is a polyphenol that is found in abundant quantities in grapes and wine. Although recent experimental data revealed the anti-cancer potency of piceatannol, the molecular mechanisms underlying the antileukemic activity have not yet been studied in detail. In the present study, we investigated further possible mechanisms by which piceatannol exerts its anti-proliferative action in cultured human leukemia U937 cells. Exposure of U937 cells to piceatannol resulted in growth inhibition and induction of apoptosis as measured by MTT assay and flow cytometry analysis, which was associated with S phase arrest of the cell cycle. Piceatannol treatment markedly inhibited the activity of telomerase, and the levels of human telomerase reverse transcriptase (hTERT) and telomerase-associated protein-1 (TEP-1), main determinants of the telomerase enzymatic activity, were progressively down-regulated by piceatannol treatment in a dose-dependent fashion. However, the levels of cyclooxygenases (COXs) expression and prostaglandin E2 (PGE2) release were not changed in piceatannol-treated U937 cells. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of piceatannol.

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참고문헌

  1. Ashikawa, K., S. Majumdar, S. Banerjee, A. C. Bharti, S. Shishodia and B. B. Aggarwal. 2002. Piceatannol inhibits TNF-induced NF-$\kappa$B activation and NF-$\kappa$B-mediated gene expression through suppression of $I\kappaB\alpha$ kinase and p65 phosphorylation. J. Immunol. 169, 6490-6497. https://doi.org/10.4049/jimmunol.169.11.6490
  2. Barton, B. E., J. G. Karras, T. F. Murphy, A. Barton and H. F. Huang. 2004. Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: Direct STAB inhibition induces apoptosis in prostate cancer lines. Mol. Cancer Ther. 3, 11-20. https://doi.org/10.1186/1476-4598-3-11
  3. Bavaresco, L., C. Fregoni, E. Cantu and M. Trevisan, 1999. Stilbene compounds: from the grapevine to wine. Drugs Exp. Clin. Res. 25, 57-63.
  4. Cerni, C. 2000. Telomeres, telomerase, and myc. An. Update. Mutat. Res. 462, 31-47. https://doi.org/10.1016/S1383-5742(99)00091-5
  5. Dempke, W., C. Rie, A. Grothey and H. J. Schmoll. 2001. Cyclooxygenase-2: a novel target for cancer chemotherapy? J. Cancer Res. Clin. Oncol. 127, 411-417. https://doi.org/10.1007/s004320000225
  6. Dwyer, J. T. 1998. Health aspects of vegetarian diets. Am. J. Clin. Nutr. 48, 712-738.
  7. Ferreira, M. J., N. Duarte, N. Gyemant, R. Radies, G. Cherepnev, A. Varga and J. Molnar. 2006. Interaction between doxorubicin and the resistance modifier stilbene on multidrug resistant mouse lymphoma and human breast cancer cells. Anticancer Res. 26, 3541-3546.
  8. Ferrigni, N. R., J. L. McLaughlin, R. G. Powell and C. R. Smith Jr. 1984. Use of potato disc and brine shrimp bio-assays to detect activity and isolate piceatannol as the antileukemic principle from the seeds of Euphorbia lagascae. J. Nat. Prod. 47, 347-352. https://doi.org/10.1021/np50032a019
  9. Geahlen, R. L. and J. L. McLaughlin. 1989. Piceatannol (3,4,3' ,5' -tetrahydroxy-trans-stilbene) is a naturally occurring protein-tyrosine kinase inhibitor. Biochem. Biophys. Res. Commun. 165, 241-245. https://doi.org/10.1016/0006-291X(89)91060-7
  10. Giercksky, K. E. 2001. COX-2 inhibition and prevention of cancer. Best Pract. Res. Clin. Gastroenterol. 15, 821-831. https://doi.org/10.1053/bega.2001.0237
  11. Han, M. H., S. O. Kim, G. Y. Kim, T. K. Kwon, B. T. Choi, W. H. Lee and Y. H. Choi. 2007. Induction of apoptosis by sanguinarine in C6 rat glioblastoma cells is associated with the modulation of the Bcl-2 family and activation of caspases through downregulation of extracellular signalregulated kinase and Akt. Anticancer Drugs 18, 913-921.
  12. Jin, C. Y., D. O. Moon, K. J. Lee, M. O. Kim, J. DF. Lee, Y. H. Choi, Y. M. Park and G. Y. Kim. 2006. Piceatannol attenuates lipopolysaccharide-induced NF-$\alpha$B activation and NF-$\alpha$B-related proinflammatory mediators in BV2 microglia. Pharmacol. Res. 54, 461-467. https://doi.org/10.1016/j.phrs.2006.09.005
  13. Kumari, A. L., A. M. Ali, S. Das, B. V. Pardhasaradhi, C. H Varalakshmi and A. Khar. 2005. Role of STAT3 and NF-$\alpha$B signaling in the serum factor-induced apoptosis in AK-5 cells. Biochem. Biophys. Res. Commun. 336, 860-867. https://doi.org/10.1016/j.bbrc.2005.08.185
  14. 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. https://doi.org/10.1038/sj.onc.1205163
  15. Larrosa, M., F. A. Tomas-Barberan and J. C. Espin. 2003. Grape polyphenol resveratrol and the related molecule 4-hydroxystilbene induce growth inhibition, apoptosis, S-phase arrest, and upregulation of cyclins A, E, and B1 in human SK-Mel-28 melanoma cells. J. Agric. Food Chem. 51, 4576-4584. https://doi.org/10.1021/jf030073c
  16. 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
  17. 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
  18. Riboli, E. and T. Norat. 2003. Epidemiologic evidence of the protective effect of fruits and vegetables on cancer risk. Am. J. Clin. Nutr. 78, 559S-569S. https://doi.org/10.1093/ajcn/78.3.559S
  19. Roupe, K., X. W. Teng, X. Fu, G. G. Meadows and N. M. Davies. 2004. Determination of piceatannol in rat serum and liver microsomes: pharmacokinetics and phase I and II biotransformation. Biomed. Chromatogr. 18, 486-491. https://doi.org/10.1002/bmc.342
  20. Sawaoka, H., S. Tsuji, M. Tsujii, E. S. Gunawan, Y. Sasaki, S. Kawano and M. Hori. 1999. Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo. Lab. Invest. 79, 1469-1477.
  21. Sherr, C. J. 2000. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res. 60, 3689-3695.
  22. Su, L. and M. David. 2000. Distinct mechanisms of STAT phosphorylation via the interferon-$\alpha$/B receptor. Selective inhibition of STAT 13 and STAT5 by piceatannol. J. Biol. Chem. 275, 12661-12666. https://doi.org/10.1074/jbc.275.17.12661
  23. Vainio, H 2001. Is COX-2 inhibition a panacea for cancer prevention? Int. J. Cancer 94, 613-614. https://doi.org/10.1002/ijc.1518
  24. Vaziri, H, M. D. West, R. C. Allsopp, T. S. Davison, Y. S. Wu, C. H. Arrowsmith, G. G. Poirier and S. Benchimol. 1997. ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly (ADP-ribose) polymerase. EMBO J. 16, 6018-6033. https://doi.org/10.1093/emboj/16.19.6018
  25. Weinberg, R. A. 1995. The retinoblastoma protein and cell cycle control. Cell 81, 323-330. https://doi.org/10.1016/0092-8674(95)90385-2
  26. Wieder, T., A. Prokop, B. Bagci, F. Essmann, D. Bernicke, K. Schulze-Osthoff, B. orken, H. G. Schmalz, P. T. Daniel and G. Henze. 2001. Piceatannol, a hydroxylated analog of the chemopreventive agent resveratrol, is a potent inducer of apoptosis in the lymphoma cell line BJAB and in primary, leukemic lymphoblasts. Leukemia 15, 1735-1742. https://doi.org/10.1038/sj.leu.2402284
  27. Yamamoto, Y. and R. B. Gaynor. 2001. Therapeutic potential of inhibition of the NF-$\alpha$B pathway in the treatment of inflammation and cancer. J. Clin. Invest. 107, 135-142. https://doi.org/10.1172/JCI11914
  28. Yoshida, A., Y. Pommier and T. Ueda. 2006. Endonuclease activation and chromosomal DNA fragmentation during apoptosis in leukemia cells. Int. J. Hematol. 84, 31-37. https://doi.org/10.1007/BF03342699

피인용 문헌

  1. Piceatannol-Induced G1 Arrest of the Cell Cycle is Associated with Inhibition of Prostaglandin E2Production in Human Gastric Cancer AGS Cells vol.41, pp.7, 2012, https://doi.org/10.3746/jkfn.2012.41.7.907
  2. Induction of Apoptosis by Piceatannol in YD-15 Human Oral Cancer Cells vol.44, pp.7, 2015, https://doi.org/10.3746/jkfn.2015.44.7.975