Journal of the Korean Society of Food Science and Nutrition (한국식품영양과학회지)

The Korean Society of Food Science and Nutrition (한국식품영양과학회)
권호 표지
DOI QR코드

DOI QR Code

Piceatannol-Induced G1 Arrest of the Cell Cycle is Associated with Inhibition of Prostaglandin E2 Production in Human Gastric Cancer AGS Cells

Piceatannol에 의한 AGS 인체 위암세포의 G1 Arrest 및 Prostaglandin E2 생성의 억제

  • Choi, Yung-Hyun (Dept. of Biochemistry, Dongeui University College of Oriental Medicine, Dept. of Biomaterial Control (BK21 Program), and Anti-Aging Research Center & Blue-Bio Industry Regional Innovation Center, Dongeui University)
  • 최영현 (동의대학교 한의과대학 생화학교실, 대학원 바이오물질제어학과(BK21 Program), 항노화연구소 및 블루바이오소재개발센터)
  • Received : 2012.03.26
  • Accepted : 2012.05.25
  • Published : 2012.07.31
Download PDF
⟨ Previous Next ⟩

Abstract

Piceatannol (trans-3,4,3',5'-tetrahydroxystilbene) is a polyphenol detected in grapes, rhubarb, and sugarcane. Although recent experimental data revealed that this compound is known to exhibit immunosuppressive and antitumorigenic activities in several cell lines, the molecular mechanisms underlying anticancer activity are poorly understood. In the present study, we investigated possible further mechanisms by which piceatannol exerts its anti-proliferative action in cultured human gastric cancer AGS cells. Piceatannol treatment resulted in the inhibition of growth and G1 arrest of the cell cycle in a concentration-dependent manner, as determined by MTT assay and flow cytometry analysis. The induction of G1 arrest by piceatannol was associated with the modulation of cyclin-dependent kinases (Cdks) and cyclins, up-regulation of the expression of Cdk inhibitor p21 (WAF1/CIP1) in both transcriptional and translational levels, and the inhibition of phosphorylation of retinoblastoma proteins and E2F1 expression. In addition, piceatannol treatment caused a progressive decrease in the expression levels of cyclooxygenase (COX)-2 without significant changes in the levels of COX-1, which was correlated with a decrease in prostaglandin $E_2$ synthesis.

포도, 대황, 사탕수수 등을 포함한 다양한 식물에서 발견되는 hydroxystilbene의 일종인 piceatannol은 암세포의 증식을 억제하고 apoptosis를 유발하는 것으로 알려져 있다. 본 연구에서는 AGS 인체위암세포를 대상으로 piceatannol에 의한 암세포 증식억제 과정에서 나타나는 또 다른 현상들을 조사하기 위하여 실시되었다. Piceatannol이 처리된 AGS 위암세포는 piceatannol의 처리 농도의 증가에 따라 생존율이 감소되었으며, 이는 세포주기 G1 arrest 유발과 연관이 있음을 MTT assay와 flow cytometry 분석을 통하여 확인하였다. Piceatannol에 의한 AGS 세포의 G1 arrest는 Cdks 및 cyclins의 발현 변화 및 Cdk 저해제인 p21의 발현을 전사 및 번역 수준에서 증가시켰으며, pRB 단백질의 인산화 감소 및 E2F1의 발현 억제와 연관성이 있었다. 아울러 piceatannol은 COX-2의 mRNA 및 단백질의 발현을 억제하였으나 COX-1의 발현에는 영향을 미치지 않았으며, piceatannol에 의한 COX-2의 발현억제는 PGE2의 생성 저하와 관련이 있었다. 본 연구의 결과는 piceatannol에 의한 세포주기 G1 arrest 유발이 COX-2의 선택적 발현 차단과 연관이 있음을 보여 주는 것이다.

Keywords

References

  1. Anderson WF, Umar A, Viner JL, Hawk ET. 2002. The role of cyclooxygenase inhibitors in cancer prevention. Curr Pharm 8: 1035-1062. https://doi.org/10.2174/1381612023394935
  2. Gately S, Kerbel R. 2003. Therapeutic potential of selective cyclooxygenase-2 inhibitors in the management of tumor angiogenesis. Prog Exp Tumor Res 37: 179-192. https://doi.org/10.1159/000071373
  3. Fujita H, Koshida K, Keller ET, Takahashi Y, Yoshimito T, Namiki M, Mizokami A. 2002. Cyclooxygenase-2 promotes prostate cancer progression. Prostate 53: 232-240. https://doi.org/10.1002/pros.10152
  4. Ferrigni NR, McLaughlin JL, Powell RG, Smith Jr CR. 1984. Use of potato disc and brine shrimp bioassays 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
  5. Bavaresco L, Fregoni C, Cantu E, Trevisan M. 1999. Stilbene compounds: from the grapevine to wine. Drugs Exp Clin Res 25: 57-63.
  6. Roupe K, Teng XW, Fu X, Meadows GG, Davies NM. 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
  7. Geahlen RL, McLaughlin JL. 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
  8. Ashikawa K, Majumdar S, Banerjee S, Bharti AC, Shishodia S, Aggarwal BB. 2002. Piceatannol inhibits TNF-induced NF-${\kappa}B$ activation and NF-${\kappa}B$-mediated gene expression through suppression of $I{\kappa}B{\alpha}$ kinase and p65 phosphorylation. J Immunol 169: 6490-6497. https://doi.org/10.4049/jimmunol.169.11.6490
  9. Kumari AL, Ali AM, Das S, Pardhasaradhi BV, Varalakshmi CH, Khar A. 2005. Role of STAT3 and NF-${\kappa}B$ 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
  10. Barton BE, Karras JG, Murphy TF, Barton A, Huang HF. 2004. Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: direct STAT3 inhibition induces apoptosis in prostate cancer lines. Mol Cancer Ther 3: 11-20. https://doi.org/10.1186/1476-4598-3-11
  11. Su L, David M. 2000. Distinct mechanisms of STAT phosphorylation via the interferon-${\alpha}/{\beta}$ receptor. Selective inhibition of STAT3 and STAT5 by piceatannol. J Biol Chem 275: 12661-12666. https://doi.org/10.1074/jbc.275.17.12661
  12. Ferreira MJ, Duarte N, Gyemant N, Radics R, Cherepnev G, Varga A, Molnar J. 2006. Interaction between doxorubicin and the resistance modifier stilbene on multidrug resistant mouse lymphoma and human breast cancer cells. Anticancer Res 26: 3541-3546.
  13. Kuo PL, Hsu YL. 2008. The grape and wine constituent piceatannol inhibits proliferation of human bladder cancer cells via blocking cell cycle progression and inducing Fas/membrane bound Fas ligand-mediated apoptotic pathway. Mol Nutr Food Res 52: 408-418. https://doi.org/10.1002/mnfr.200700252
  14. Larrosa M, Tomás-Barberán FA, Espín JC. 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
  15. Larrosa M, Tomás-Barberán FA, Espín JC. 2004. The grape and wine polyphenol piceatannol is a potent inducer of apoptosis in human SK-Mel-28 melanoma cells. Eur J Nutr 43: 275-284. https://doi.org/10.1007/s00394-004-0471-5
  16. Lee B, Lee EJ, Kim DI, Park SK, Kim WJ, Moon SK. 2009. Inhibition of proliferation and migration by piceatannol in vascular smooth muscle cells. Toxicol In Vitro 23: 1284-1291. https://doi.org/10.1016/j.tiv.2009.07.023
  17. Wieder T, Prokop A, Bagci B, Essmann F, Bernicke D, Schulze-Osthoff K, Dorken B, Schmalz HG, Daniel PT, Henze G. 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
  18. Jin CY, Moon DO, Lee KJ, Kim MO, Lee JD, Choi YH, Park YM, Kim GY. 2006. Piceatannol attenuates lipopolysaccharide- induced NF-${\kappa}B$ activation and NF-${\kappa}B$-related proinflammatory mediators in BV2 microglia. Pharmacol Res 54: 461-467. https://doi.org/10.1016/j.phrs.2006.09.005
  19. Choi YH. 2008. Induction of S phase arrest of the cell cycle by piceatannol is associated with inhibition of telomerase activity in human leukemic U937 cells. J Life Sci 18: 96-102. https://doi.org/10.5352/JLS.2008.18.1.096
  20. Kim YH, Park C, Lee JO, Kim GY, Lee WH, Choi YH, Ryu CH. 2008. Induction of apoptosis by piceatannol in human leukemic U937 cells through down-regulation of Bcl-2 and activation of caspases. Oncol Rep 19: 961-967.
  21. Kang CH, Moon DO, Choi YH, Choi IW, Moon SK, Kim WJ, Kim GY. 2011. Piceatannol enhances TRAIL-induced apoptosis in human leukemia THP-1 cells through Sp1- and ERK-dependent DR5 up-regulation. Toxicol in Vitro 25: 605-612. https://doi.org/10.1016/j.tiv.2010.12.006
  22. Sherr CJ. 2000. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res 60: 3689-3695.
  23. Lee YM, Lim DY, Cho HJ, Seon MR, Kim JK, Lee BY, Park JH. 2009. Piceatannol, a natural stilbene from grapes, induces G1 cell cycle arrest in androgen-insensitive DU145 human prostate cancer cells via the inhibition of CDK activity. Cancer Lett 285: 166-173. https://doi.org/10.1016/j.canlet.2009.05.011
  24. Fritzer-Szekeres M, Savinc I, Horvath Z, Saiko P, Pemberger M, Graser G, Bernhaus A, Ozsvar-Kozma M, Grusch M, Jaeger W, Szekeres T. 2008. Biochemical effects of piceatannol in human HL-60 promyelocytic leukemia cellssynergism with Ara-C. Int J Oncol 33: 887-892.
  25. Girard F, Strausfeld U, Fernandez A, Lamb NJ. 1991. Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell 67: 1169-1179. https://doi.org/10.1016/0092-8674(91)90293-8
  26. Brandeis M, Hunt T. 1996. The proteolysis of mitotic cyclins in mammalian cells persists from the end of mitosi until the onset of S phase. EMBO J 15: 5280-5289.
  27. Elledge SJ, Harper JW. 1994. Cdk inhibitors: on the threshold of checkpoints and development. Curr Opin Cell Biol 6: 847-852. https://doi.org/10.1016/0955-0674(94)90055-8
  28. Morgan DO. 1995. Principles of CDK regulation. Nature 374: 131-134. https://doi.org/10.1038/374131a0
  29. Son PS, Park SA, Na HK, Jue DM, Kim S, Surh YJ. 2010. Piceatannol, a catechol-type polyphenol, inhibits phorbol ester-induced NF-${\kappa}B$ activation and cyclooxygenase-2 expression in human breast epithelial cells: cysteine 179 of IKK$\beta$ as a potential target. Carcinogenesis 31: 1442-1449. https://doi.org/10.1093/carcin/bgq099
  30. Liu D, Kim DH, Park JM, Na HK, Surh YJ. 2009. Piceatannol inhibits phorbol ester-induced NF-kB activation and COX-2 expression in cultured human mammary epithelial cells. Nutr Cancer 61: 855-863. https://doi.org/10.1080/01635580903285080
  31. Djoko B, Chiou RY, Shee JJ, Liu YW. 2007. Characterization of immunological activities of peanut stilbenoids, arachidin- 1, piceatannol, and resveratrol on lipopolysaccharideinduced inflammation of RAW 264.7 macrophages. J Agric Food Chem 55: 2376-2383. https://doi.org/10.1021/jf062741a

Cited by

  1. 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