Betulinic Acid, a Naturally Occurring Triterpene found in the Bark of the White Birch Tree induces Apoptotic Cell Death in KB Cervical Cancer Cells through Specificity Protein 1 and its Downstream

  • Shin, Ji-Ae (Department of Oral Pathology, School of Dentistry, Institute of Oral Bioscience, Brain Korea 21, Chonbuk National University) ;
  • Choi, Eun-Sun (Department of Oral Pathology, School of Dentistry, Institute of Oral Bioscience, Brain Korea 21, Chonbuk National University) ;
  • Jung, Ji-Youn (Department of Companion and Laboratory Animal Science, Kongju National University) ;
  • Cho, Nam-Pyo (Department of Oral Pathology, School of Dentistry, Institute of Oral Bioscience, Brain Korea 21, Chonbuk National University) ;
  • Cho, Sung-Doe (Department of Oral Pathology, School of Dentistry, Institute of Oral Bioscience, Brain Korea 21, Chonbuk National University)
  • 투고 : 2011.04.07
  • 심사 : 2011.05.18
  • 발행 : 2011.06.30

초록

흰자작나무의 껍질에서 발견된 자연적으로 발생한 triterpene 인 betulinic acid (BA)가 다양한 종류의 암세포와 동물 모델에서 세포사멸을 유도하는 것으로 알려져 있다. 하지만 자궁경부암세포에서 BA의 화학적 암예방 효과는 연구되지 않은 상태이다. 따라서 이 연구에서는 사람 자궁경부암세포주인 KB세포를 이용하여, BA가 세포증식을 감소시키고 세포사멸을 유도하는 것을 확인하였다. KB 세포에서 BA에 의해 유도되는 세포증식의 억제는 specificity protein 1 (Sp1)과 Sp1의 표적단백질인 myeloid cell leukemia-1 (Mcl-1) 그리고 survivin의 감소 때문인 것으로 확인되었다. 따라서 BA는 자궁경부암에서 과다 발현되는 Sp1을 조절하는 새로운 화학적 암예방 물질로서 작용할 수 있을 것으로 생각된다.

Betulinic acid (BA), a naturally occurring triterpene found in the bark of the white birch tree, has been investigated to induce apoptosis in various cancer cells and animal models. However, there is no report of the chemopreventive effect of BA in cervical cancer cells. Using KB human cervical cancer cells as a model, we currently show that BA decreases cell viability and induces apoptotic cell death. The mechanism of the BA-induced anti-growth response in KB cells is due to the down-regulation of specificity protein 1 (Sp 1) and its downstream targets, myeloid cell leukemia-1(Mcl-1) and survivin. Thus, BA acts as a novel chemopreventive agent through the regulation of Sp1 that is highly expressed in tumors.

키워드

참고문헌

  1. Parkin, D. M., Bray, F., Ferlay, J., Pisani, P.: Global cancer statistics, 2002. CA Cancer J Clin 55(2),74-108 (2005). https://doi.org/10.3322/canjclin.55.2.74
  2. Monk, B. J., Sill, M. W., McMeekin, D. S., Cohn, D. E., Ramondetta, L. M., Boardman, C. H., Benda, J., Cella, D.: Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 27(28), 4649-4655 (2009). https://doi.org/10.1200/JCO.2009.21.8909
  3. Moore, D. H., Blessing, J. A., McQuellon, R. P., Thaler, H. T., Cella, D., Benda, J., Miller, D. S., Olt, G., King, S., Boggess, J. F.: Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 22(15), 3113-3119 (2004). https://doi.org/10.1200/JCO.2004.04.170
  4. Papineni, S., Chintharlapalli, S., Abdelrahim, M., Lee, S. O., Burghardt, R., Abudayyeh, A., Baker, C., Herrera, L., Safe, S.: Tolfenamic acid inhibits esophageal cancer through repression of specificity proteins and c-Met. Carcinogenesis 30(7), 1193-1201 (2009). https://doi.org/10.1093/carcin/bgp092
  5. Abdelrahim, M., Baker, C. H., Abbruzzese, J. L., Safe, S.: Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. J Natl Cancer Inst 98(12), 855-868 (2006). https://doi.org/10.1093/jnci/djj232
  6. Alakurtti, S., Makela, T., Koskimies, S., Yli-Kauhaluoma, J: Pharmacological properties of the ubiquitous natural product betulin. Eur J Pharm Sci 29(1), 1-13 (2006).
  7. Pisha, E., Chai, H., Lee, I. S., Chagwedera, T. E., Farnsworth, N. R., Cordell, G. A., Beecher, C. W., Fong, H. H., Kinghorn, A. D., Brown, D. M.: Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat Med 1(10), 1046-1051 (1995). https://doi.org/10.1038/nm1095-1046
  8. Chintharlapalli, S., Papineni, S., Ramaiah, S. K., Safe, S.: Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res 67(6), 2816-2823 (2007). https://doi.org/10.1158/0008-5472.CAN-06-3735
  9. Fulda, S., Jeremias, I., Steiner, H. H., Pietsch, T., Debatin, K.M.: Betulinic acid: a new cytotoxic agent against malignant brain-tumor cells. Int J Cancer 82(3), 435-441 (1999). https://doi.org/10.1002/(SICI)1097-0215(19990730)82:3<435::AID-IJC18>3.0.CO;2-1
  10. Schmidt, M. L., Kuzmanoff, K. L., Ling-Indeck, L., Pezzuto, J. M.: Betulinic acid induces apoptosis in human neuroblastoma cell lines. Eur J Cancer 33(12), 2007-2010 (1997). https://doi.org/10.1016/S0959-8049(97)00294-3
  11. Rzeski, W., Stepulak, A., Szymanski, M., Sifringer, M., Kaczor, J., Wejksza, K., Zdzisinska, B., Kandefer-Szerszen, M.: Betulinic acid decreases expression of bcl-2 and cyclin D1, inhibits proliferation, migration and induces apoptosis in cancer cells. Naunyn Schmiedebergs Arch Pharmacol 374(1), 11-20 (2006). https://doi.org/10.1007/s00210-006-0090-1
  12. Eichenmuller, M., Hemmerlein, B., von Schweinitz, D., Kappler, R.: Betulinic acid induces apoptosis and inhibits hedgehog signalling in rhabdomyosarcoma. Br J Cancer 103(1), 43-51 (2010). https://doi.org/10.1038/sj.bjc.6605715
  13. Pandey, M. K., Sung, B., Aggarwal, B. B.: Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP-1 in human multiple myeloma cells. Int J Cancer 127(2), 282-292 (2010).
  14. Zannetti, A., Del Vecchio, S., Carriero, M. V., Fonti, R., Franco, P., Botti, G., D'Aiuto, G., Stoppelli, M. P., Salvatore, M.: Coordinate up-regulation of Sp1 DNA-binding activity and urokinase receptor expression in breast carcinoma. Cancer Res 60(6), 1546-1551 (2000).
  15. Chiefari, E., Brunetti, A., Arturi, F., Bidart, J. M., Russo, D., Schlumberger, M., Filetti, S.: Increased expression of AP2 and Sp1 transcription factors in human thyroid tumors: a role in NIS expression regulation? BMC Cancer 2:35 (2002). https://doi.org/10.1186/1471-2407-2-35
  16. Wang, L., Wei, D., Huang, S., Peng, Z., Le, X., Wu, T. T., Yao, J., Ajani, J., Xie, K.: Transcription factor Sp1 expression is a significant predictor of survival in human gastric cancer. Clin Cancer Res 9(17), 6371-6380 (2003).
  17. Hosoi, Y., Watanabe, T., Nakagawa, K., Matsumoto, Y., Enomoto, A., Morita, A., Nagawa, H., Suzuki, N.: Up-regulation of DNA-dependent protein kinase activity and Sp1 in colorectal cancer. Int J Oncol 25(2), 461-468 (2004).
  18. Yao, J. C., Wang, L., Wei, D., Gong, W., Hassan, M., Wu, T. T., Mansfield, P., Ajani, J., Xie, K.: Association between expression of transcription factor Sp1 and increased vascular endothelial growth factor expression, advanced stage, and poor survival in patients with resected gastric cancer. Clin Cancer Res 10(12 Pt 1), 4109-4117 (2004). https://doi.org/10.1158/1078-0432.CCR-03-0628
  19. Lou, Z., O'Reilly, S., Liang, H., Maher, V. M., Sleight, S. D., McCormick, J. J.: Down-regulation of overexpressed sp1 protein in human fibrosarcoma cell lines inhibits tumor formation. Cancer Res 65(3),1007-1017 (2005).
  20. Safe, S., Abdelrahim, M.: Sp transcription factor family and its role in cancer. Eur J Cancer 41(16), 2438-2448 (2005). https://doi.org/10.1016/j.ejca.2005.08.006
  21. Shim, J. H., Shin, J. A., Jung, J. Y., Choi, K. H., Choi, E. S., Cho, N. P., Kong, G., Ryu, M. H., Chae, J. I., Cho, S. D.: Chemopreventive effect of tolfenamic acid on KB human cervical cancer cells and tumor xenograft by downregulating specificity protein 1. Eur J Cancer Prev 20(2), 102-111 (2011). https://doi.org/10.1097/CEJ.0b013e328341e38f