DOI QR코드

DOI QR Code

SP-8356, a (1S)-(-)-Verbenone Derivative, Inhibits the Growth and Motility of Liver Cancer Cells by Regulating NF-κB and ERK Signaling

  • Kim, Dong Hwi (Department of Biomedical Science, Korea University College of Medicine) ;
  • Yong, Hyo Jeong (Department of Biomedical Science, Korea University College of Medicine) ;
  • Mander, Sunam (Department of Biomedical Science, Korea University College of Medicine) ;
  • Nguyen, Huong Thi (Department of Biomedical Science, Korea University College of Medicine) ;
  • Nguyen, Lan Phuong (Department of Biomedical Science, Korea University College of Medicine) ;
  • Park, Hee-Kyung (Department of Biomedical Science, Korea University College of Medicine) ;
  • Cha, Hyo Kyeong (Department of Biomedical Science, Korea University College of Medicine) ;
  • Kim, Won-Ki (Department of Biomedical Science, Korea University College of Medicine) ;
  • Hwang, Jong-Ik (Department of Biomedical Science, Korea University College of Medicine)
  • 투고 : 2020.11.05
  • 심사 : 2020.12.10
  • 발행 : 2021.05.01

초록

Liver cancer is a common tumor and currently the second leading cause of cancer-related mortality globally. Liver cancer is highly related to inflammation as more than 90% of liver cancer arises in the context of hepatic inflammation, such as hepatitis B virus and hepatitis C virus infection. Despite significant improvements in the therapeutic modalities for liver cancer, patient prognosis is not satisfactory due to the limited efficacy of current drug therapies in anti-metastatic activity. Therefore, developing new effective anti-cancer agents with anti-metastatic activity is important for the treatment of liver cancer. In this study, SP-8356, a verbenone derivative with anti-inflammatory activity, was investigated for its effect on the growth and migration of liver cancer cells. Our findings demonstrated that SP-8356 inhibits the proliferation of liver cancer cells by inducing apoptosis and suppressing the mobility and invasion ability of liver cancer cells. Functional studies revealed that SP-8356 inhibits the mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways, which are related to cell proliferation and metastasis, resulting in the downregulation of metastasis-related genes. Moreover, using an orthotopic liver cancer model, tumor growth was significantly decreased following treatment with SP-8356. Thus, this study suggests that SP-8356 may be a potential agent for the treatment of liver cancer with multimodal regulation.

키워드

참고문헌

  1. Arii, S., Mise, M., Harada, T., Furutani, M., Ishigami, S., Niwano, M., Mizumoto, M., Fukumoto, M. and Imamura, M. (1996) Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology 24, 316-322. https://doi.org/10.1053/jhep.1996.v24.pm0008690399
  2. Bruix, J. and Sherman, M.; American Association for the Study of Liver Diseases (2011) Management of hepatocellular carcinoma: an update. Hepatology 53, 1020-1022. https://doi.org/10.1002/hep.24199
  3. Chaffer, C. L. and Weinberg, R. A. (2011) A perspective on cancer cell metastasis. Science 331, 1559. https://doi.org/10.1126/science.1203543
  4. Chambard, J. C., Lefloch, R., Pouyssegur, J. and Lenormand, P. (2007) ERK implication in cell cycle regulation. Biochim. Biophys. Acta 1773, 1299-1310. https://doi.org/10.1016/j.bbamcr.2006.11.010
  5. Chan, C. F., Yau, T. O., Jin, D. Y., Wong, C. M., Fan, S. T. and Ng, I. O. (2004) Evaluation of nuclear factor-kappaB, urokinase-type plasminogen activator, and HBx and their clinicopathological significance in hepatocellular carcinoma. Clin. Cancer Res. 10, 4140-4149. https://doi.org/10.1158/1078-0432.CCR-03-0574
  6. Chen, L., Li, M., Li, Q., Wang, C. J. and Xie, S. Q. (2013) DKK1 promotes hepatocellular carcinoma cell migration and invasion through β-catenin/MMP7 signaling pathway. Mol. Cancer 12, 157. https://doi.org/10.1186/1476-4598-12-157
  7. Choi, I. Y., Lim, J. H., Hwang, S., Lee, J. C., Cho, G. S. and Kim, W. K. (2010) Anti-ischemic and anti-inflammatory activity of (S)-cisverbenol. Free. Radic. Res. 44, 541-551. https://doi.org/10.3109/10715761003667562
  8. Coussens, L. M. and Werb, Z. (2002) Inflammation and cancer. Nature 420, 860-867. https://doi.org/10.1038/nature01322
  9. El-Serag, H. B. and Rudolph, K. L. (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132, 2557-2576. https://doi.org/10.1053/j.gastro.2007.04.061
  10. Flores, K. and Seger, R. (2013) Stimulated nuclear import by β-like importins. F1000Prime Rep. 5, 41. https://doi.org/10.12703/p5-41
  11. Hoesel, B. and Schmid, J. A. (2013) The complexity of NF-κB signaling in inflammation and cancer. Mol. Cancer 12, 86. https://doi.org/10.1186/1476-4598-12-86
  12. Huber, M. A., Azoitei, N., Baumann, B., Grbnert, S., Sommer, A., Pehamberger, H., Kraut, N., Beug, H. and Wirth, T. (2004) NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J. Clin. Invest. 114, 569-581. https://doi.org/10.1172/JCI200421358
  13. Je, Y., Schutz, F. A. B. and Choueiri, T. K. (2009) Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. Lancet Oncol. 10, 967-974. https://doi.org/10.1016/s1470-2045(09)70222-0
  14. Ju, C., Song, S., Hwang, S., Kim, C., Kim, M., Gu, J., Oh, Y. K., Lee, K., Kwon, J., Lee, K., Kim, W. K. and Choi, Y. (2013) Discovery of novel (1S)-(-)-verbenone derivatives with anti-oxidant and antiischemic effects. Bioorg. Med. Chem. Lett. 23, 5421-5425. https://doi.org/10.1016/j.bmcl.2013.07.038
  15. Kuo, C. F., Su, J. D., Chiu, C. H., Peng, C. C., Chang, C. H., Sung, T. Y., Huang, S. H., Lee, W. C. and Chyau, C. C. (2011) Anti-inflammatory effects of supercritical carbon dioxide extract and its isolated carnosic acid from Rosmarinus officinalis leaves. J. Agric. Food Chem. 59, 3674-3685. https://doi.org/10.1021/jf104837w
  16. Li, W., Tan, D., Zenali, M. J. and Brown, R. E. (2009) Constitutive activation of nuclear factor-kappa B (NF-kB) signaling pathway in fibrolamellar hepatocellular carcinoma. Int. J. Clin. Exp. Pathol. 3, 238-243.
  17. Lin, Y., Liu, J., Huang, Y., Liu, D., Zhang, G. and Kan, H. (2017) microRNA-489 plays an anti-metastatic role in human hepatocellular carcinoma by targeting matrix metalloproteinase-7. Transl. Oncol. 10, 211-220. https://doi.org/10.1016/j.tranon.2017.01.010
  18. Liu, P., Cheng, H., Roberts, T. M. and Zhao, J. J. (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov. 8, 627-644. https://doi.org/10.1038/nrd2926
  19. Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J. F., De Oliveira, A. C., Santoro, A., Raoul, J. L., Forner, A., Schwartz, M., Porta, C., Zeuzem, S., Bolondi, L., Greten, T. F., Galle, P. R., Seitz, J. F., Borbath, I., Haeussinger, D., Giannaris, T., Shan, M., Moscovici, M., Voliotis, D. and Bruix, J. (2008) Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378-390. https://doi.org/10.1056/NEJMoa0708857
  20. Mander, S., Kim, D. H., Thi Nguyen, H., Yong, H. J., Pahk, K., Kim, E. Y., Lee, K., Seong, J. Y., Kim, W. K. and Hwang, J. I. (2019) SP8356, a (1S)-(-)-verbenone derivative, exerts in vitro and in vivo anti-breast cancer effects by inhibiting NF-κB signaling. Sci. Rep. 9, 6595. https://doi.org/10.1038/s41598-019-41224-y
  21. Marrero, C. R. and Marrero, J. A. (2007) Viral hepatitis and hepatocellular carcinoma. Arch. Med. Res. 38, 612-620. https://doi.org/10.1016/j.arcmed.2006.09.004
  22. Min, C., Eddy, S. F., Sherr, D. H. and Sonenshein, G. E. (2008) NF-kappaB and epithelial to mesenchymal transition of cancer. J. Cell. Biochem. 104, 733-744. https://doi.org/10.1002/jcb.21695
  23. Min, L., He, B. and Hui, L. (2011) Mitogen-activated protein kinases in hepatocellular carcinoma development. Semin. Cancer Biol. 21, 10-20. https://doi.org/10.1016/j.semcancer.2010.10.011
  24. Nakagawa, H. and Maeda, S. (2012) Inflammation- and stress-related signaling pathways in hepatocarcinogenesis. World J. Gastroenterol. 18, 4071-4081. https://doi.org/10.3748/wjg.v18.i31.4071
  25. Naugler, W. E. and Karin, M. (2008) NF-κB and cancer-identifying targets and mechanisms. Curr. Opin. Genet. Dev. 18, 19-26. https://doi.org/10.1016/j.gde.2008.01.020
  26. Okusaka, T., Okada, S., Ishii, H., Nose, H., Nagahama, H., Nakasuka, H., Ikeda, K. and Yoshimori, M. (1997) Prognosis of hepatocellular carcinoma patients with extrahepatic metastases. Hepatogastroenterology 44, 251-257.
  27. Ola, M. S., Nawaz, M. and Ahsan, H. (2011) Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol. Cell. Biochem. 351, 41-58. https://doi.org/10.1007/s11010-010-0709-x
  28. Pahk, K., Noh, H., Joung, C., Jang, M., Song, H. Y., Kim, K. W., Han, K., Hwang, J. I., Kim, S. and Kim, W. K. (2019) A novel CD147 inhibitor, SP-8356, reduces neointimal hyperplasia and arterial stiffness in a rat model of partial carotid artery ligation. J. Transl. Med. 17, 274. https://doi.org/10.1186/s12967-019-2024-y
  29. Pikarsky, E., Porat, R. M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E. and BenNeriah, Y. (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461-466. https://doi.org/10.1038/nature02924
  30. Plotnikov, A., Flores, K., Maik-Rachline, G., Zehorai, E., Kapri-Pardes, E., Berti, D. A., Hanoch, T., Besser, M. J. and Seger, R. (2015) The nuclear translocation of ERK1/2 as an anticancer target. Nat. Commun. 6, 6685. https://doi.org/10.1038/ncomms7685
  31. Plotnikov, A., Zehorai, E., Procaccia, S. and Seger, R. (2011) The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim. Biophys. Acta 1813, 1619-1633. https://doi.org/10.1016/j.bbamcr.2010.12.012
  32. Poddar, N., Ramlal, R., Ravulapati, S., Devlin, S. M., Gadani, S., Vidal, C. I., Cao, D., Befeler, A. S. and Lai, J. (2017) Extrahepatic metastasis of hepatocellular carcinoma arising from a hepatic adenoma without concurrent intrahepatic recurrence. Curr. Oncol. 24, e333-e336.
  33. Ranjan, A., Iyer, S. V., Ward, C., Link, T., Diaz, F. J., Dhar, A., Tawfik, O. W., Weinman, S. A., Azuma, Y., Izumi, T. and Iwakuma, T. (2018) MTBP inhibits the Erk1/2-Elk-1 signaling in hepatocellular carcinoma. Oncotarget 9, 21429-21443. https://doi.org/10.18632/oncotarget.25117
  34. Saharinen, P., Eklund, L., Pulkki, K., Bono, P. and Alitalo, K. (2011) VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol. Med. 17, 347-362. https://doi.org/10.1016/j.molmed.2011.01.015
  35. Siegel, R. L., Miller, K. D. and Jemal, A. (2018) Cancer statistics, 2018. CA Cancer J. Clin. 68, 7-30. https://doi.org/10.3322/caac.21442
  36. Singh, A. K., Kumar, R. and Pandey, A. K. (2018) Hepatocellular Carcinoma: causes, mechanism of progression and biomarkers. Curr. Chem. Genom. Transl. Med. 12, 9-26. https://doi.org/10.2174/2213988501812010009
  37. Tong, R., Yang, B., Xiao, H., Peng, C., Hu, W., Weng, X., Cheng, S., Du, C., Lv, Z., Ding, C., Zhou, L., Xie, H., Wu, J. and Zheng, S. (2017) KCTD11 inhibits growth and metastasis of hepatocellular carcinoma through activating Hippo signaling. Oncotarget 8, 37717-37729. https://doi.org/10.18632/oncotarget.17145
  38. Torre, L. A., Bray, F., Siegel, R. L., Ferlay, J., Lortet-Tieulent, J. and Jemal, A. (2015) Global cancer statistics. CA Cancer J. Clin. 2012. 65, 87-108. https://doi.org/10.3322/caac.21262
  39. Tung-Ping Poon, R., Fan, S. T. and Wong, J. (2000) Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann. Surg. 232, 10-24. https://doi.org/10.1097/00000658-200007000-00003
  40. Uchino, K., Tateishi, R., Shiina, S., Kanda, M., Masuzaki, R., Kondo, Y., Goto, T., Omata, M., Yoshida, H. and Koike, K. (2011) Hepatocellular carcinoma with extrahepatic metastasis: clinical features and prognostic factors. Cancer 117, 4475-4483. https://doi.org/10.1002/cncr.25960
  41. Uka, K., Aikata, H., Takaki, S., Shirakawa, H., Jeong, S. C., Yamashina, K., Hiramatsu, A., Kodama, H., Takahashi, S. and Chayama, K. (2007) Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma. World J. Gastroenterol. 13, 414-420. https://doi.org/10.3748/wjg.v13.i3.414
  42. Ulisse, S., Baldini, E., Sorrenti, S. and D'armiento, M. (2009) The urokinase plasminogen activator system: a target for anti-cancer therapy. Curr. Cancer Drug Targets 9, 32-71. https://doi.org/10.2174/156800909787314002
  43. Valastyan, S. and Weinberg, R. A. (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275-92. https://doi.org/10.1016/j.cell.2011.09.024
  44. Wang, J., Huang, Q. and Chen, M. (2003) The role of NF-kappaB in hepatocellular carcinoma cell. Chin. Med. J. 116, 747-752.
  45. Wu, J. M., Sheng, H., Saxena, R., Skill, N. J., Bhat-Nakshatri, P., Yu, M., Nakshatri, H. and Maluccio, M. A. (2009) NF-kappaB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy. Cancer Lett. 278, 145-155. https://doi.org/10.1016/j.canlet.2008.12.031
  46. Yao, D. F., Wu, X. H., Zhu, Y., Shi, G. S., Dong, Z. Z., Yao, D. B., Wu, W., Qiu, L. W. and Meng, X. Y. (2005) Quantitative analysis of vascular endothelial growth factor, microvascular density and their clinicopathologic features in human hepatocellular carcinoma. Hepatobiliary Pancreat. Dis. Int. 4, 220-226.
  47. Yeh, C. B., Hsieh, M. J., Hsieh, Y. H., Chien, M. H., Chiou, H. L. and Yang, S. F. (2012) Antimetastatic effects of norcantharidin on hepatocellular carcinoma by transcriptional inhibition of MMP-9 through modulation of NF-kB activity. PLoS ONE 7, e31055. https://doi.org/10.1371/journal.pone.0031055
  48. Zhu, Y. J., Zheng, B., Wang, H. Y. and Chen, L. (2017) New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol. Sin. 38, 614-622. https://doi.org/10.1038/aps.2017.5

피인용 문헌

  1. SP-1154, a novel synthetic TGF-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice vol.145, 2021, https://doi.org/10.1016/j.biopha.2021.112441