Effects of Caffeic Acid Methyl Ester from Mentha arvensis Linne var. piperascens on Function of E6 Oncoprotein of HPV 16

박하에서 분리한 Caffeic Acid Methyl Ester가 자궁경부암 바이러스 발암단백질 E6의 기능에 미치는 영향

  • Baek, Tae-Woong (Laboratory of Cell Biology, Korea Research Institute of Bioscience and Biotechnology) ;
  • Lee , Kyung-Ae (Laboratory of Cell Biology, Korea Research Institute of Bioscience and Biotechnology) ;
  • Ahn , Min-Jung (Laboratory of Cell Biology, Korea Research Institute of Bioscience and Biotechnology) ;
  • Joo, Hae-Hyung (Laboratory of Cell Biology, Korea Research Institute of Bioscience and Biotechnology) ;
  • Oh , Hyun-Cheol (Laboratory of Cell Biology, Korea Research Institute of Bioscience and Biotechnology) ;
  • Ahn , Jong-Seok (Laboratory of Cell Biology, Korea Research Institute of Bioscience and Biotechnology) ;
  • Cho , Yong-Kweon (Department of Healthscience and Biochemistry, Changwon National University) ;
  • Myung , Pyung-Keun (Department of Pharmacy, College of Pharmacy Chungnam National University) ;
  • Yoon, Do-Young (Laboratory of Cell Biology, Korea Research Institute of Bioscience and Biotechnology)
  • 백태웅 (한국생명공학연구원 세포생물학연구실) ;
  • 이경애 (한국생명공학연구원 세포생물학연구실) ;
  • 안민정 (한국생명공학연구원 세포생물학연구실) ;
  • 주혜경 (한국생명공학연구원 세포생물학연구실) ;
  • 오현철 (한국생명공학연구원 세포생물학연구실) ;
  • 안종석 (한국생명공학연구원 세포생물학연구실) ;
  • 조용권 (창원대학교 보건생화학과) ;
  • 명평근 (충남대학교 약학과) ;
  • 윤도영 (한국생명공학연구원 세포생물학연구실)
  • Published : 2004.01.01

Abstract

Cervical cancer is one of the leading causes of female death. Viral oncoproteins E6 and E7 are selectively retained and expressed in carcinoma cells infected with HPV (Human pa pilloma virus) type 16 and cooperated in immotalization and transformation of primary keratinocyte. E6 and E7 oncoproteins interfere the functions of tumor suppressor proteins p53 and retinoblasoma protein (pRb), respectively. Among a lots of natural products, Mentha arvensis Linne var.piperascens have inhibitory effects on bindings between E6 oncoprotein and tumor suppressor p53, E3 ubiqutin- protein ligase (E6AP). HPV oncoprotein inhibitors from Mentha piperita L. were isolated by solvent partition and column chromatography (Silica gel, RP-18) and inhibitory compounds were finally purified by HPLC using an ELISA screening system based on binding between E6 and E6AP. The aim of this study is to identify the structure of inhibitory compounds and to investigate whether these compounds have inhibitory effects on functions of E6 oncoprotein. We investigated whether caffeic acid methyl ester (CAM) extracted from Mentha piperita L. could inhibit the function of E6 oncoprotein. CAM inhibited the in vitro binding of E6 and E6AP which are essential for the binding and degradation of the tumor suppressor p53 and also inhibited the proliferation of human cervical cancer cell lines (SiHa and CaSKi) in a dose response manner. These results suggest that CAM inhibited the function of E6 oncoprotein, suggesting that it can be used as a potential drug for the treatment of cervical cancers infected with HPV.

Keywords

References

  1. Hubbert, N. L., Sedman, S. A. and Schiller, J. T. : Human papillomavirus type 16 E6 increases the degradation rare of p53 in human Keratinocyte. J. Virol. 66, 6237 (1992)
  2. zur Hausen, H. and de Villiers, E. M. : Human papillomavirus infections in nonmelanoma skin cancers from renal transplant recipients and nonimmunosuppressed patients. J. Natl. Cancer. Inst. 88, 802 (1996) https://doi.org/10.1093/jnci/88.12.802
  3. Scheffner, M. K., Munger, K., Byrne, J. C. and Howley, P. M. : The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc. Natl. Acad. Sci. USA 88, 5523 (1991)
  4. Woodworth, C. D., Cheng, S., Simpson, S., Hamache, L., Chow, L. T., Broker, T. R. and DiPaolo, J. A. : Recombinant retroviruses encoding human papillomavirus type 18 E6 and E7 genes stimulate proliferation and delay differentiation of human keratinocytes early after infection. Oncogene. 7, 619 (1992)
  5. Scheffer, M., Huibergtse. J. M. and Howley, P. M. : Identification of human ubiqutin-conjugating enzyme that mediates the E6AP-dependent of p53. Proc. Natl. Acad. Sci. USA 91, 8797 (1994)
  6. Sherman, L., Jackman, A., Itzhaki, H., Stoppler, M. C., Koval, D. and Schegel, M. : Inhibition of serum- and calcium-induced differentition of human keratinocytes by HPV 16 E6 oncopro-tein : role of p53 inactivation. Virology 237, 296 (1997) https://doi.org/10.1006/viro.1997.8778
  7. 안덕균 : 원색한국본초도감, 교학사 (1998)
  8. 이영노 : 원색한국식물도감, 교학사 (1998)
  9. 이우철 : 원색한국기준식물도감, 아카데미서적 (1996)
  10. 이창복 : 대한식물도감, 향문사 (1980)
  11. 이휘재 : 한국식물도감, 문교부 (1961)
  12. 박종희 : 상용약용식물도감, 신일상사 (2000)
  13. Huibregtse, J., Scheffner, M. and Howley, P. M. : Cloning and expresion of the cDNAfor E6-AP, a protein that mediates the interaction of the himan papillomavirus E6 oncoprotein with p53. Mol Cell Biol. 16, 775 (1993)
  14. Huibregtse, J., Scheffner, M. and Howley, P. M. : Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins. Mol. Cell. Bio. 16, 4918 (1993)
  15. Cho, Y. S., Cho, C. W. and Yoon, D. Y. : Development of a screening system for drug against human papillomavirus-associated cervacal cancer : based on E7-Rb biding. J. Biochem. Mol. Biol. 34, 80 (2001)
  16. Cho, Y. S., Cho, C. W. and Yoon, D. Y. : Development of a screening system for drug against human papillomavirus-associated cervacal cancer: based on E6-E6AP bindig. Antiviral. Res. 47, 199 (2000)
  17. Tazaki, H., Kawabata, J. and Fujita, T. : Novel oxidative dimer from caffeic acid. Biosci. Biotichnol. Biochem. 67, 1185 (2003) https://doi.org/10.1271/bbb.67.1185
  18. Takenaka, M., Yan, X., Ono, H., Yoshida, M., Nagata, T. and Nakanishi, T. : Caffeic acid derivatives in the roots of yacon (Smallanthus sonchifolius). J. Agric. Food. Chem. 51, 793 (2003) https://doi.org/10.1021/jf020735i
  19. Lim, E. K., Higgins, G.S., Li, Y. and Bowles, D. J. Regioselectivity of glucosylation of caffeic acid by a UDP-glucose: glucosyltransferase is maintained in planta. Biochem. J. 373, 987 (2003) https://doi.org/10.1042/BJ20021453
  20. Hoeneisen, M., Alarcon, J., Aqueveque, P., Bittner, M., Becerra, J., Silva, M. and Jakupovic, J. : New caffeic acid esters from Plazia daphnoides. Z. Naturforsch. [C]. 58, 39 (2003).
  21. Gibbons, S. and Mathew, K. T. : A caffeic acid ester from Halocnemum strobilaceum. Phytochemistry 51, 465 (1999) https://doi.org/10.1016/S0031-9422(99)00007-2
  22. Lee, H. K. : In vitro anticomplementary activity of phenyl-propanoids from agastache rugosa. Kor. J. Pharmacogn. 27, 20 (1996)
  23. Oh, S. O., Jung, K. Y. and Lee, H. K. : In vitro anticomple-mentary of phenylpropanoids from agastache rugosa. Kor. J. Pharmacogn. 27, 20 (1996)