식방풍 유래 화합물 3′,4′-Disenecioylkhellactone의 위암세포에서 STAT3 활성화 억제를 매개로 하는 세포사멸 유도작용

3′,4′-Disenecioylkhellactone from Peucedanum japonicum Thunb. Induces Apoptosis Mediated by Inhibiting STAT3 Signaling in Human Gastric Cancer Cells

  • 투고 : 2018.08.09
  • 심사 : 2018.09.10
  • 발행 : 2018.09.30

초록

3',4'-Disenecioylkhellactone is one of khellactone-type coumarins isolated from the roots of Peucedanum japonicum Thunb. However, its pharmacological effects are still little understood. In the present study, we investigated the inhibitory effect of 3',4'-disenecioylkhellactone on growth of gastric cancer cells. 3',4'-Disenecioylkhellactone strongly suppressed cell proliferation and induced caspase-mediated apoptosis in AGS human gastric cancer cells. Analysis of phospho-antibody arrays revealed 3',4'-disenecioylkhellactone effectively suppressed signal transducer and activator of transcription 3 (STAT3) tyrosine phosphorylation. 3',4'-Disenecioylkhellactone decreased STAT3 translocation to the nucleus and expression of STAT3 target genes. In addition, we examined the level of STAT3 activation in several gastric cancer cells and found that the inhibition of STAT3 phosphorylation by 3',4'-disenecioylkhellactone was associated with gastric cancer cell proliferation. Taken together, this study provides evidence for the first time that 3',4'-disenecioylkhellactone may be a potential therapeutic agent for the prevention or treatment of gastric cancer.

키워드

참고문헌

  1. Leung, W. K., Wu, M. S., Kakugawa, Y., Kim, J. J., Yeoh, K. G., Goh, K. L., Wu, K. C., Wu, D. C., Sollano, J., Kachintorn, U., Gotoda, T., Lin, J. T., You, W. C., Ng, E. K., Sung, J. J. and Asia Pacific Working Group on Gastric Cancer (2008) Screening for gastric cancer in Asia: current evidence and practice. Lancet Oncol. 9: 279-287. https://doi.org/10.1016/S1470-2045(08)70072-X
  2. Washington, K. (2010) 7th edition of the AJCC cancer staging manual: stomach. Ann. Surg. Oncol. 17: 3077-3079. https://doi.org/10.1245/s10434-010-1362-z
  3. Jung, K. W., Won, Y. J., Kong, H. J., Lee, E. S. and Community of Population-Based Regional Cancer Registries (2018) Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2015. Cancer Res. Treat. 50: 303-316. https://doi.org/10.4143/crt.2018.143
  4. Eom, B. W., Joo, J., Kim, S., Shin, A., Yang, H. R., Park, J., Choi, I. J., Kim, Y. W., Kim, J. and Nam, B. H. (2015) Prediction model for gastric cancer incidence in Korean population. PLoS One 10: e0132613. https://doi.org/10.1371/journal.pone.0132613
  5. Smyth, E. C., Verheij, M., Allum, W., Cunningham, D., Cervantes, A. and Arnold, D. (2016) Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 27: v38-v49. https://doi.org/10.1093/annonc/mdw350
  6. Yu, H. and Jove, R. (2004) The STATs of cancer-new molecular targets come of age. Nat. Rev. Cancer 4: 97-105. https://doi.org/10.1038/nrc1275
  7. Chai, E. Z., Shanmugam, M. K., Arfuso, F., Dharmarajan, A., Wang, C., Kumar, A. P., Samy, R. P., Lim, L. H., Wang, L., Goh, B. C., Ahn, K. S., Hui, K. M. and Sethi, G. (2016) Targeting transcription factor STAT3 for cancer prevention and therapy. Pharmacol. Ther. 162: 86-97. https://doi.org/10.1016/j.pharmthera.2015.10.004
  8. Son, H. K., Kang, S. T., Jung, H. O. and Lee, J. J. (2013) Changes in physicochemical properties of Peucedanum japonicum Thunb. after blanching. Korean J. Food Preserv. 20: 628-635. https://doi.org/10.11002/kjfp.2013.20.5.628
  9. Kim, S. J., Chin, Y. W., Yoon, K. D., Ryu, M. Y., Yang, M. H., Lee, J. H. and Kim, J. (2008) Chemical Constituents of Saposhnikovia divaricata. Kor. J. Pharmacogn. 39: 357-364.
  10. Hong, M. J. and Kim, J. (2017) Determination of the absolute configuration of khellactone esters from Peucedanum japonicum roots. J. Nat. Prod. 80: 1354-1360. https://doi.org/10.1021/acs.jnatprod.6b00947
  11. Chen, I. S., Chang, C. T., Sheen, W. S., Teng, C. M., Tsai, I. L., Duh, C. Y. and Ko, F. N. (1996) Coumarins and antiplatelet aggregation constituents from Formosan Peucedanum japonicum. Phytochemistry 41: 525-530. https://doi.org/10.1016/0031-9422(95)00625-7
  12. Jung, H. K., Sim, M. O., Jang, J. H., Kim, T. M., An, B. K., Kim, M. S. and Jung, W. S. (2016) Anti-obesity effects of Peucedanum japonicum Thunberg L. on 3T3-L1 cells and high-fat diet-induced obese mice. Korean J. Plant Resour. 29: 1-10. https://doi.org/10.7732/kjpr.2016.29.1.001
  13. Zheng, M., Jin, W., Son, K. H., Chang, H. W., Kim, H. P., Bae, K. H. and Kang, S. S. (2005) The constituents isolated from Peucedanum japonicum Thunb. and their cyclooxygenase (COX) inhibitory activity. Korean J. Med. Crop Sci. 13: 75-79.
  14. Nunez, G., Benedict, M. A., Hu, Y. and Inohara, N. (1998) Caspases: the proteases of the apoptotic pathway. Oncogene 17: 3237-3245. https://doi.org/10.1038/sj.onc.1202581
  15. Fan, T. J., Han, L. H., Cong, R. S. and Liang, J. (2005) Caspase family proteases and apoptosis. Acta Biochim. Biophys. Sin. 37: 719-727. https://doi.org/10.1111/j.1745-7270.2005.00108.x
  16. Blume-Jensen, P. and Hunter, T. (2001) Oncogenic kinase signalling. Nature 411: 355-365. https://doi.org/10.1038/35077225
  17. Jing, N. and Tweardy, D. J. (2005) Targeting Stat3 in cancer therapy. Anticancer Drugs 16: 601-607. https://doi.org/10.1097/00001813-200507000-00002
  18. Gritsko, T., Williams, A., Turkson, J., Kaneko, S., Bowman, T., Huang, M., Nam, S., Eweis, I., Diaz, N., Sullivan, D., Yoder, S., Enkemann, S., Eschrich, S., Lee, J. H., Beam, C. A., Cheng, J., Minton, S., Muro-Cacho, C. A. and Jove, R. (2006) Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin. Cancer. Res. 12: 11-19. https://doi.org/10.1158/1078-0432.CCR-04-1752
  19. Xu, D. and Qu, C. K. (2008) Protein tyrosine phosphatases in the JAK/STAT pathway. Front. Biosci. 13: 4925-4932.