Biochemistry (Moscow)

, Volume 82, Issue 8, pp 933–941 | Cite as

Nigericin inhibits epithelial ovarian cancer metastasis by suppressing the cell cycle and epithelial−mesenchymal transition

  • Wen Wang
  • Yan Zhao
  • Shujuan Yao
  • Xiujuan Cui
  • Wenying Pan
  • Wenqian Huang
  • Jiangang Gao
  • Taotao Dong
  • Shiqian Zhang


Epithelial ovarian cancer (EOC) has the highest mortality among various types of gynecological malignancies. Most patients die of metastasis and recurrence due to cisplatin resistance. Thus, it is urgent to develop novel therapies to cure this disease. CCK-8 assay showed that nigericin exhibited strong cytotoxicity on A2780 and SKOV3 cell lines. Flow cytometry indicated that nigericin could induce cell cycle arrest at G0/G1 phase and promote cell apoptosis. Boyden chamber assay revealed that nigericin could inhibit migration and invasion in a dose-dependent manner by suppressing epithelial–mesenchymal transition (EMT) in EOC cells. These effects were mediated, at least partly, by the Wnt/β-catenin signaling pathway. Our results demonstrated that nigericin could inhibit EMT during cell invasion and metastasis through the canonical Wnt/β-catenin signaling pathway. Nigericin may prove to be a novel therapeutic strategy that is effective in patients with metastatic EOC.


epithelial ovarian cancer nigericin cell cycle epithelial–mesenchymal transition 



epithelial–mesenchymal transition


epithelial ovarian cancer


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Siegel, R., Naishadham, D., and Jemal, A. (2012) Cancer statistics, 2012, Cancer J. Clin., 62, 10–29.CrossRefGoogle Scholar
  2. 2.
    Siegel, R., Ward, E., Brawley, O., and Jemal, A. (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths, Cancer J. Clin., 61, 212–236.CrossRefGoogle Scholar
  3. 3.
    Vergara, D., Merlot, B., Lucot, J. P., Collinet, P., Vinatier, D., Fournier, I., and Salzet, M. (2010) Epithelial-mesenchymal transition in ovarian cancer, Cancer Lett., 291, 59–66.CrossRefPubMedGoogle Scholar
  4. 4.
    Davidson, B., Trope, C. G., and Reich, R. (2012) Epithelial-mesenchymal transition in ovarian carcinoma, Front. Oncol., 2, 33.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Huang, R. Y., Chung, V. Y., and Thiery, J. P. (2012) Targeting pathways contributing to epithelial-mesenchymal transition (EMT) in epithelial ovarian cancer, Curr. Drug Targets, 13, 1649–1653.CrossRefPubMedGoogle Scholar
  6. 6.
    Turley, E. A., Veiseh, M., Radisky, D. C., and Bissell, M. J. (2008) Mechanisms of disease: epithelial-mesenchymal transition–does cellular plasticity fuel neoplastic progression? Nat. Clin. Pract. Oncol., 5, 280–290.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Thiery, J. P. (2002) Epithelial-mesenchymal transitions in tumour progression, Nat. Rev. Cancer, 2, 442–454.CrossRefPubMedGoogle Scholar
  8. 8.
    Vaupel, P. (2004) Tumor microenvironmental physiology and its implications for radiation oncology, Semin. Radiat. Oncol., 14, 198–206.CrossRefPubMedGoogle Scholar
  9. 9.
    Lu, D., Choi, M. Y., Yu, J., Castro, J. E., Kipps, T. J., and Carson, D. A. (2011) Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells, Proc. Natl. Acad. Sci. USA, 108, 13253–13257.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Zhou, H. M., Dong, T. T., Wang, L. L., Feng, B., Zhao, H. C., Fan, X. K., and Zheng, M. H. (2012) Suppression of colorectal cancer metastasis by nigericin through inhibition of epithelial-mesenchymal transition, World J. Gastroenterol., 18, 2640–2648.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Xu, S., and Gotlieb, A. I. (2013) Wnt3a/beta-catenin increases proliferation in heart valve interstitial cells, Cardiovasc. Pathol., 22, 156–166.CrossRefPubMedGoogle Scholar
  12. 12.
    Goodell, M. A. (2005) Stem cell identification and sorting using the Hoechst 33342 side population (SP), Curr. Protoc. Cytom., Chapt. 9, Unit 9.18.Google Scholar
  13. 13.
    Yilmaz, M., and Christofori, G. (2009) EMT, the cytoskeleton, and cancer cell invasion, Cancer Metastasis Rev., 28, 15–33.CrossRefPubMedGoogle Scholar
  14. 14.
    Sung, P. L., Jan, Y. H., Lin, S. C., Huang, C. C., Lin, H., Wen, K. C., Chao, K. C., Lai, C. R., Wang, P. H., Chuang, C. M., Wu, H. H., Twu, N. F., Yen, M. S., Hsiao, M., and Huang, C. Y. (2016) Periostin in tumor microenvironment is associated with poor prognosis and platinum resistance in epithelial ovarian carcinoma, Oncotarget, 7, 4036–4047.CrossRefPubMedGoogle Scholar
  15. 15.
    Gupta, P. B., Onder, T. T., Jiang, G., Tao, K., Kuperwasser, C., Weinberg, R. A., and Lander, E. S. (2009) Identification of selective inhibitors of cancer stem cells by high-throughput screening, Cell, 138, 645–659.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Yi, B. R., Kim, T. H., Kim, Y. S., and Choi, K. C. (2015) Alteration of epithelial-mesenchymal transition markers in human normal ovaries and neoplastic ovarian cancers, Int. J. Oncol., 46, 272–280.PubMedGoogle Scholar
  17. 17.
    Fernando, G., Paul, F., Laura, J., Alejandra, A. M., Gabriela, M., and Alberto, P. L. (2016) Is the Wnt/beta catenin signalling pathway activated in seminoma? An immunohistochemical study, J. Cancer Res. Ther., 12, 1075–1079.CrossRefPubMedGoogle Scholar
  18. 18.
    Yang, C., Du, W., and Yang, D. (2016) Inhibition of green tea polyphenol EGCG((–)-epigallocatechin-3-gallate) on the proliferation of gastric cancer cells by suppressing canonical Wnt/beta-catenin signalling pathway, Int. J. Food Sci. Nutr., 67, 818–827.CrossRefPubMedGoogle Scholar
  19. 19.
    Mittag, S., Valenta, T., Weiske, J., Bloch, L., Klingel, S., Gradl, D., Wetzel, F., Chen, Y., Petersen, I., Basler, K., and Huber, O. (2016) A novel role for the tumour suppressor Nitrilase1 modulating the Wnt/beta-catenin signalling pathway, Cell Discov., 2, 15039.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Van Zuylen, W. J., Rawlinson, W. D., and Ford, C. E. (2016) The Wnt pathway: a key network in cell signalling dysregulated by viruses, Rev. Med. Virol., 26, 340–355.CrossRefPubMedGoogle Scholar
  21. 21.
    Patel, S., Doble, B., and Woodgett, J. R. (2004) Glycogen synthase kinase-3 in insulin and Wnt signalling: a doubleedged sword? Biochem. Soc. Trans., 32, 803–808.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mashima, T. (2017) Cancer stem cells (CSCs) as a rational therapeutic cancer target, and screening for CSC-targeting drugs, Yakugaku Zasshi, 137, 129–132.CrossRefPubMedGoogle Scholar
  23. 23.
    Najumudeen, A. K., Jaiswal, A., Lectez, B., Oetken-Lindholm, C., Guzman, C., Siljamaki, E., Posada, I. M., Lacey, E., Aittokallio, T., and Abankwa, D. (2016) Cancer stem cell drugs target K-ras signaling in a stemness context, Oncogene, 35, 5248–5262.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Wei, Z., Liu, Y., Wang, Y., Zhang, Y., Luo, Q., Man, X., Wei, F., and Yu, X. (2016) Downregulation of Foxo3 and TRIM31 by miR-551b in side population promotes cell proliferation, invasion, and drug resistance of ovarian cancer, Med. Oncol., 33, 126.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2017

Authors and Affiliations

  • Wen Wang
    • 1
    • 2
  • Yan Zhao
    • 1
    • 3
  • Shujuan Yao
    • 2
  • Xiujuan Cui
    • 2
  • Wenying Pan
    • 1
    • 4
  • Wenqian Huang
    • 1
  • Jiangang Gao
    • 5
  • Taotao Dong
    • 1
  • Shiqian Zhang
    • 1
  1. 1.Department of Obstetrics and GynecologyQilu Hospital, Shandong UniversityJinan, ShandongP.R. China
  2. 2.Department of Obstetrics and GynecologyTengzhou Central People’s HospitalTengzhou, ShandongP.R. China
  3. 3.Department of Obstetrics and GynecologyLinyi People’s HospitalLinyi, ShandongP.R. China
  4. 4.Department of Obstetrics and GynecologyBinzhou Medical School Affiliated HospitalBinzhou, ShandongP.R. China
  5. 5.School of Life ScienceShandong UniversityJinan, ShandongP.R. China

Personalised recommendations