Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Anti-Proliferative Activity of Nodosin, a Diterpenoid from Isodon serra, via Regulation of Wnt/β-Catenin Signaling Pathways in Human Colon Cancer Cells

  • Bae, Eun Seo (College of Pharmacy, Natural Products Research Institute, Seoul National University) ;
  • Kim, Young-Mi (College of Pharmacy, Research Institute of Pharmaceutical Science, Seoul National University) ;
  • Kim, Dong-Hwa (College of Pharmacy, Natural Products Research Institute, Seoul National University) ;
  • Byun, Woong Sub (College of Pharmacy, Natural Products Research Institute, Seoul National University) ;
  • Park, Hyen Joo (College of Pharmacy, Natural Products Research Institute, Seoul National University) ;
  • Chin, Young-Won (College of Pharmacy, Research Institute of Pharmaceutical Science, Seoul National University) ;
  • Lee, Sang Kook (College of Pharmacy, Natural Products Research Institute, Seoul National University)
  • Received : 2020.01.13
  • Accepted : 2020.04.20
  • Published : 2020.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Colorectal cancer (CRC) is one of the most malignant type of cancers and its incidence is steadily increasing, due to life style factors that include western diet. Abnormal activation of canonical Wnt/β-catenin signaling pathway plays an important role in colorectal carcinogenesis. Therefore, targeting Wnt/β-catenin signaling has been considered a crucial strategy in the discovery of small molecules for CRC. In the present study, we found that Nodosin, an ent-kaurene diterpenoid isolated from Isodon serra, effectively inhibits the proliferation of human colon cancer HCT116 cells. Mechanistically, Nodosin effectively inhibited the overactivated transcriptional activity of β-catenin/T-cell factor (TCF) determined by Wnt/β-catenin reporter gene assay in HEK293 and HCT116 cells. The expression of Wnt/β-catenin target genes such as Axin2, cyclin D1, and survivin were also suppressed by Nodosin in HCT116 cells. Further study revealed that a longer exposure of Nodosin induced the G2/M phase cell cycle arrest and subsequently apoptosis in HCT116 cells. These findings suggest that the anti-proliferative activity of Nodosin in colorectal cancer cells might in part be associated with the regulation of Wnt/β-catenin signaling pathway.

Keywords

References

  1. Behrens, J., Jerchow, B. A., Wurtele, M., Grimm, J., Asbrand, C., Wirtz, R., Kuhl, M., Wedlich, D. and Birchmeier, W. (1998) Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science 280,596-599. https://doi.org/10.1126/science.280.5363.596
  2. Byun, W. S., Kim, W. K., Han, H. J., Chung, H. J., Jang, K., Kim, H. S., Kim, S., Kim, D., Bae, E. S., Park, S., Lee, J., Park, H. G. and Lee, S. K. (2019) Targeting histone methyltransferase DOT1L by a novel psammaplin a analog inhibits growth and metastasis of triple-negative breast cancer. Mol. Ther. Oncolytics. 15,140-152. https://doi.org/10.1016/j.omto.2019.09.005
  3. Byun, W. S., Jin, M., Yu, J., Kim, W. K., Song, J., Chung, H. J., Jeong, L. S. and Lee, S. K. (2018) A novel selenonucleoside suppresses tumor growth by targeting Skp2 degradation in paclitaxel-resistant prostate cancer. Biochem. Pharmacol. 158, 84-94. https://doi.org/10.1016/j.bcp.2018.10.002
  4. Chen, C., Chen, Y., Zhu, H., Xiao, Y., Zhang, X., Zhao, J. and Chen, Y. (2014) Effective compoundsscreening from Rabdosiaserra (Maxim) HaraagainstHBV and tumor in vitro. Int. J. Clin. Exp.Med. 7, 384-392.
  5. Fodde, R., Smits, R. and Clevers, H. (2001) APC, signal transduction and genetic instability in colorectal cancer. Nat. Rev. Cancer. 1, 55-67. https://doi.org/10.1038/35094067
  6. He, X., Semenov, M., Tamai, K. and Zeng, X. (2004) LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development 131, 1663-1677. https://doi.org/10.1242/dev.01117
  7. Hua, Y., Yang, Y., Li, Q., He, X., Zhu, W., Wang, J. and Gan, X. (2018) Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical $WNT/{\beta}$-catenin pathway. J. Biol. Chem. 51, 19710-19724.
  8. Jung, C., Hong, J., Bae, S. Y., Kang, S. S., Park, H. J. and Lee, S. K. (2015) Antitumor activity of americanin A isolated from the seeds of Phytolacca americana by regulating the ATM/ATR signaling pathway and the Skp2-p27 axis in human colon cancer cells. J. Nat. Prod. 78, 2983-2993. https://doi.org/10.1021/acs.jnatprod.5b00743
  9. Kang, J. I., Hong, J. Y., Choi, J. S. and Lee, S. K. (2016) Columbianadin inhibits cell proliferation by inducing apoptosis and necroptosis in HCT116 colon cancer cells. Biomol. Ther. (Seoul) 24, 320-327. https://doi.org/10.4062/biomolther.2015.145
  10. Kang, Y. J., Park, H. J., Chung, H. J., Min, H. Y., Park, E. J., Lee, M. A., Shin, Y. and Lee, S. K. (2012) $Wnt/{\beta}$-catenin signaling mediates the antitumor activity of magnolol in colorectal cancer cells. Mol. Pharmacol. 82, 168-177. https://doi.org/10.1124/mol.112.078535
  11. Kim, W. K., Bach, D. H., Ryu, H. W., Oh, J., Park, H. J., Hong, J. Y., Song, H. H., Eum, S., Bach, T. T. and Lee, S. K. (2017) Cytotoxic activities of Telectadium dongnaiense and its constituents by inhibition of the $Wnt/{\beta}$-catenin signaling pathway. Phytomedicine 34, 136-142. https://doi.org/10.1016/j.phymed.2017.08.008
  12. Kim, W. K., Byun, W. S., Chung, H. J., Oh, J., Park, H. J., Choi, J. S. and Lee, S. K. (2018) Esculetin suppresses tumor growth and metastasis by targeting Axin2/E-cadherin axis in colorectal cancer. Biochem. Pharmacol. 152, 71-83. https://doi.org/10.1016/j.bcp.2018.03.009
  13. Kim, W. K., Pyee, Y., Chung, H. J., Park, H. J., Hong, J. Y., Son, K. H. and Lee, S. K. (2016) Antitumor activity of spicatoside A by modulation of autophagy and apoptosis in human colorectal cancer cells. J. Nat. Prod. 79, 1097-1104. https://doi.org/10.1021/acs.jnatprod.6b00006
  14. Kobayashi, M., Honma, T., Matsuda, Y., Suzuki, Y., Narisawa, R., Ajioka, Y. and Asakura, H. (2000) Nuclear translocation of beta-catenin in colorectal cancer. Br. J. Cancer. 82, 1689-1693. https://doi.org/10.1054/bjoc.1999.1112
  15. Komiya, Y. and Habas, R. (2008) Wnt signal transduction pathways. Organogenesis 4, 68-75. https://doi.org/10.4161/org.4.2.5851
  16. Lee, E., Salic, A., Krüger, R., Heinrich, R. and Kirschner, M. W. (2003) The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway. PLoS Biol. 1, e10. https://doi.org/10.1371/journal.pbio.0000010
  17. Li, J., Du, J., Sun, L., Liu, J. and Quan, Z. (2010) Anti-inflammatory function of Nodosin via inhibition of IL-2. Am. J. Chin. Med. 38, 127-142. https://doi.org/10.1142/S0192415X10007713
  18. MacDonald, B. T., Tamai, K. and He, X. (2009) $Wnt/{\beta}$-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17, 9-26. https://doi.org/10.1016/j.devcel.2009.06.016
  19. Maharjan, S., Park, B. K., Lee, S. I., Lim, Y., Lee, K., Lee, Y. and Kwon, H. J. (2019) Gomisin G suppresses the growth of colon cancer cells by attenuation of AKT phosphorylation and arrest of cell cycle progression. Biomol. Ther. (Seoul) 27, 210-215. https://doi.org/10.4062/biomolther.2018.054
  20. Pai, S. G., Carneiro, B. A., Mota, J. M., Costa, R., Leite, C. A., Barroso-Sousa, R., Kaplan, J. B., Chae, Y. K. and Giles, F. J. (2017) Wnt/beta-cateninpathway: modulating anticancerimmuneresponse. J. Hematol. Oncol. 10, 101-112. https://doi.org/10.1186/s13045-017-0471-6
  21. Reya, T. and Clevers, H. (2005) Wnt signalling in stem cells and cancer. Nature 434, 843-850. https://doi.org/10.1038/nature03319
  22. Satooka, H., Isobe, T., Nitoda, T. and Kubo, I. (2012) Melanogenesis inhibitors from Rabdosia japonica. Phytomedicine 19, 1016-1023. https://doi.org/10.1016/j.phymed.2012.05.007
  23. Schatoff, E. M., Leach, B. I. and Dow, L. E. (2017) Wnt signaling and colorectal cancer. Curr. Colorectal. Cancer. Rep. 13, 101-110. https://doi.org/10.1007/s11888-017-0354-9
  24. Siegel, R. L., Miller, K. D. and Jemal, A. (2019) Cancer statistics, 2019. CA Cancer J. Clin. 69, 7-34. https://doi.org/10.3322/caac.21551
  25. Sun, H. D., Hsuang, S. X. and Han, Q. B. (2006) Diterpenoids from Isodonspecies and their biologicalactivities. Nat. Prod. Rep. 23, 673-698. https://doi.org/10.1039/b604174d
  26. Tolwinski, N. S. and Wieschaus, E. A. (2004) A nuclear function for armadillo/beta-catenin. PLoS Biol. 2, e95. https://doi.org/10.1371/journal.pbio.0020095
  27. Wang, C. F., Wang, Z. Y., Tao, S. F., Ding, J., Sun, L. J., Li, J. Y. and Quan, Z. W. (2012) Preconditioning donor liver with Nodosin perfusion lessens rat ischemia reperfusion injury via heme oxygenase-1 upregulation. J. Gastroenterol. Hepatol. 27, 832-840. https://doi.org/10.1111/j.1440-1746.2011.06966.x
  28. Willems, A. R., Schwab, M. and Tyers, M. (2004) A hitchhiker's guide to the cullin ubiquitin ligases: SCF and its kin. Biochim. Biophys. Acta 1695, 133-170. https://doi.org/10.1016/j.bbamcr.2004.09.027
  29. Yan, F. L., Guo, L. Q., Bai, S. P. and Sun, H. D. (2008) Two new diterpenoids and other constituents from Isodon nervosus. J. Chin. Chem. Soc. 55, 933-936. https://doi.org/10.1002/jccs.200800138
  30. Yang, K., Wang, X., Zhang, H., Wang, Z., Nan, G., Li, Y., Zhang, F., Mohammed, M. K., Haydon, R. C., Luu, H. H., Bi, Y. and He, T. C. (2016) The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: implications in targeted cancer therapies. Lab. Invest. 96, 116-136. https://doi.org/10.1038/labinvest.2015.144
  31. Yao, C. W., Kang, K. A., Piao, M. J., Ryu, Y. S., Fernando, P. M. D. J., Oh, M. C., Park, J. E., Shilnikova, K., Na, S. Y., Jeong, S. U., Boo, S. J. and Hyun, J. W. (2017) Reduced autophagy in 5-fluorouracil resistant colon cancer cells. Biomol. Ther. (Seoul) 25, 315-320. https://doi.org/10.4062/biomolther.2016.069
  32. Yoshida, N., Kinugasa, T., Ohshima, K., Yuge, K., Ohchi, T., Fujino, S., Shiraiwa, S., Katagiri, M. and Akagi, Y. (2015) Analysis of Wnt and $\beta$-catenin expression in advanced colorectal cancer. Anticancer Res. 35, 4403-4410.
  33. Zhan, T., Rindtorff, N. and Boutros, M. (2017) Wnt signaling in cancer. Oncogene 36, 1461-1473. https://doi.org/10.1038/onc.2016.304
  34. Zhang, Y., Liu, J., Jia, W., Zhao, A. and Li, T. (2005) Distinct immunosuppressive effect by Isodon serra extracts. Int. Immunopharmacol. 5, 1957-1965. https://doi.org/10.1016/j.intimp.2005.06.016

Cited by

  1. Antitumor Activity of Asperphenin B by Induction of Apoptosis and Regulation of Glyceraldehyde-3-phosphate Dehydrogenase in Human Colorectal Cancer Cells vol.84, pp.3, 2020, https://doi.org/10.1021/acs.jnatprod.0c01155
  2. Antitumor Activity of Pulvomycin via Targeting Activated-STAT3 Signaling in Docetaxel-Resistant Triple-Negative Breast Cancer Cells vol.9, pp.4, 2020, https://doi.org/10.3390/biomedicines9040436