Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Bee Venom-induced Growth Inhibition of Human Lung Cancer Cells was Associated with Inhibition of Prostagladin E2 Production and Telomerase Activity.

인체폐암세포에서 봉독에 의한 prostagladin E2 생성 및 telomerase 활성 저하

  • Kim, Jong-Hwan (Departments of Internal Medicine, College of Oriental Medicine, Dong-Eui University) ;
  • Hwang, Won-Deuk (Departments of Internal Medicine, College of Oriental Medicine, Dong-Eui University) ;
  • Kim, Byung-Woo (Department of Biomaterial Control (BK21 program), Graduate School, Dong-Eui University) ;
  • Choi, Yung-Hyun (Departments of Biochemistry, College of Oriental Medicine, Dong-Eui University)
  • 김종환 (동의대학교 한의과대학 신계내과학교실) ;
  • 황원덕 (동의대학교 한의과대학 신계내과학교실) ;
  • 김병우 (동의대학교 대학원 바이오물질제어학과) ;
  • 최영현 (동의대학교 한의과대학 생화학교실)
  • Published : 2009.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

In modern oriental medicine, bee venom therapy is being used for aqua-acupuncture to relieve pain and to cure inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and gout. Bee venom therapy has been processed and reported in many experimental studies, with regard to its effects on pain alleviation, anti-inflammation, removal of fever, anti-convulsion, suppression of tumor and immunity strengthening, etc., however, its mechanism of action, molecular targeting on prostaglandin $E_2$ ($PGE_2$) production and telomere length regulation in human cancer remains unclear. In this study, we investigated the effect of bee venom on the levels of cyclooxygenases (COXs) and telomere regulatory components of A549 human lung cancer cells. Bee venom-induced anti-proliferative effects of A549 cells were associated with the inhibition of human telomerase reverse transcriptase (hTERT) as well as human telomerase RNA (hTR), transcription factor c-myc and the activity of telomerase. In addition, bee venom 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. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of bee venom.

본 연구에서는 봉독의 처리에 따른 A549 폐암세포의 증식억제에서 $PGE_2$ 생성 및 telomerase 활성의 변화 관련성을 조사하였다. A549 세포의 증식은 봉독 처리에 의하여 유의적으로 감소되었으며, 이는 apoptosis 유발과 연관성이 있음을 알 수 있었다. 봉독 처리 농도의 증가에 따라 COX-2의 발현이 전사 및 번역 수준에서 모두 감소되었으며 이에 따른 $PGE_2$의 생성이 현저하게 감소되었으나, COX-1의 발현에는 큰 변화가 없었다. 또한 봉독 처리에 따라 telomere 조절인자들 중, hTERT, hTR 및 c-myc의 발현이 억제되었으며, telomerase의 활성도 매우 감소되었다. 본 연구의 결과는 $PGE_2$ 생성과 telomerase 활성 저하가 봉독의 항암 작용 표적인자로서 작용될 수 있음을 보여준다.

Keywords

References

  1. Ahn, C. B., C. W. Im, C. H. Kim, H. M. Youn, K. J. Jang, C. H. Song, and Y. H. Choi. 2004. Apoptotic cell death by melittin through induction of Bax and activation of caspase proteases in human lung carcinoma cells. J. Kor. Acupuncture Moxibustion Soc. 21, 41-55
  2. Ahn, C. B., C. W. Im, H. M. Youn, S. J. Park, and Y. H. Choi. 2003. Melittin-induced apoptosis is associated with inhibition of COX-2 and hTERT expression in human lung carcinoma A549 cells. J. Kor. Acupuncture Moxibustion Soc. 20, 93-106
  3. Assem, E. S. and G. Atkinson. 1973. Histamine release by MCDP (401), a peptide from the venom of the honey bee. Bri. Pharmacol. 48, 337-338
  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. Choi, Y. H. 2005. Anti-proliferative effects of bee venom through induction of Bax and Cdk inhibitor p21WAF1/CIP1 in human lung carcinoma cells. Kor. J. Oriental Physiol. Pathol. 19, 167-173
  6. 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
  7. Habermann, E. 1971. Chemistry, pharmacology and toxicology of bee, wasp and hornet venoms. In venomous animals and their venoms. pp. 3-61, Academic Press
  8. Hwang, D. Y., H. H. Kim, C. J. Kim, and E. H. Kim. 2003. Bee venom induces apoptosis and inhibits COX-2 in human osteosarcoma cell line MG-63. J. Kor. Acupuncture Moxibustion Soc. 20, 63-74
  9. Jang, M. H., M. C. Shin, S. Lim, S. M. Han, H. J. Park, I. Shin, J. S. Lee, K. A. Kim, E. H. Kim, and C. J. Kim. 2003. Bee venom induces apoptosis and inhibits expression of cyclooxygenase- 2 mRNA in human lung cancer cell line NCI-H1299. J. Pharmacol. 91, 95-104 https://doi.org/10.1254/jphs.91.95
  10. Kwon, K. R., H. K. Hoh, and C. H. Kim. 1994. The study of the introduction of bee venom acupuncture, biochemistry and pharmachology have been obtained the following results. J. Kor. Acupuncture Moxibustion Soc. 11, 159-171
  11. 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
  12. Martikainen, P., K. Nyman, and T. J. Nevalainen. 1993. Toxic effects of human pancreatic and snake and bee venom phospholipases A2 on MCF-7 cells in culture. Toxicon 31, 835-843 https://doi.org/10.1016/0041-0101(93)90218-8
  13. Moon, D. O., S. Y. Park, M. S. Heo, K. C. Kim, C. Park, W. S. Ko, Y. H. Choi, and G. Y. Kim. 2006. Key regulators in bee venom-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of ERK and Akt. Int. Immunopharmacol. 6, 1796-1807 https://doi.org/10.1016/j.intimp.2006.07.027
  14. 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
  15. Orsolic, N., L. Sver, S. Verstovsek, S. Terzic, and I. Basic. 2003. Inhibition of mammary carcinoma cell proliferation in vitro and tumor growth in vivo by bee venom. Toxicon 41, 861-870 https://doi.org/10.1016/S0041-0101(03)00045-X
  16. 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
  17. Spoerri, P. E. 1973. Apamin from bee venom. Neurobiology 3, 207-214
  18. 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-$_KB$ activation. Mutat. Res. 480-481, 243-268
  19. 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
  20. Tu, W. C., C. C. Wu, H. L. Hsieh, C. Y. Chen, and S. L. Hsu. 2008. Honeybee venom induces calcium-dependent but caspase-independent apoptotic cell death in human melanoma A2058 cells. Toxicon 52, 318-329 https://doi.org/10.1016/j.toxicon.2008.06.007
  21. Woo, H. J., H. J. Kim, S. H. Hong, S. H. Hong, B. T. Choi, Y. T. Lee, D. I. Park, and Y. H. Choi. 2007. Induction of apoptosis by bee venom in A549 human lung epithelial cancer cells through modulation of Bcl-2 and IAP family and activation of caspases. J. Life Sci. 17, 1596-1600 https://doi.org/10.5352/JLS.2007.17.11.1596
  22. Yeo, S. W., J. C. Seo, Y. H. Choi, and K. J. Jang. 2003. Induction of the growth inhibition and apoptosis by bee venom in human breast carcinoma MCF-7 cells. J. Kor. Acupuncture Moxibustion Soc. 20, 45-62, 2003