Open Access

Niclosamide inhibits colon cancer progression through downregulation of the Notch pathway and upregulation of the tumor suppressor miR-200 family

  • Authors:
    • Mohammed A. Suliman
    • Zhenxing Zhang
    • Heya Na
    • Ailton L.L. Ribeiro
    • Yu Zhang
    • Bachir Niang
    • Abdu Salim Hamid
    • Hua Zhang
    • Lijie Xu
    • Yunfei Zuo
  • View Affiliations

  • Published online on: July 22, 2016     https://doi.org/10.3892/ijmm.2016.2689
  • Pages: 776-784
  • Copyright: © Suliman et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Colorectal cancer (CRC) is among the most frequent causes of cancer-related deaths worldwide. Thus, there is a need for the development of new therapeutic approaches for the treatment of CRC. Accumulating evidence has revealed that niclosamide, an anthelminthic drug, exerts antitumor activity in several types of cancer, including colon cancer. However, the underlying molecular mechanisms responsible for the effects of this drug remain elusive. Previous studies have shown that the aberrant Notch signaling pathway contributes to the carcinogenesis of colon cancer. Herein, we examined the effects of niclosamide on the growth, migration and apoptosis of colon cancer cells, and the role of the Notch signaling pathway. By performing MTT, wound-healing and Transwell migration assays, we observed that niclosamide suppressed the growth and migration of colon cancer cells, and flow cytometry demonstrated that cell apoptosis was induced. This was associated with the decreased protein expression of Notch1, Notch2, Notch3 and Hey1, and the increased expression of the tumor suppressor microRNA (miR or miRNA)‑200 family members (miR‑200a, miR-200b, miR-200c, miR-141 and miR-429) that are typically downregulated in colon cancer. Collectively, these findings demonstrate that niclosamide potentially inhibits the progression of colon cancer by downregulating Notch signaling and by upregulating the miR-200 family members.

References

1 

Brenner H, Kloor M and Pox CP: Colorectal cancer. Lancet. 383:1490–1502. 2014. View Article : Google Scholar

2 

Miyamoto S, Nakanishi M and Rosenberg DW: Suppression of colon carcinogenesis by targeting Notch signaling. Carcinogenesis. 34:2415–2423. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Katoh M and Katoh M: Notch signaling in gastrointestinal tract (Review). Int J Oncol. 30:247–251. 2007.

4 

Prasetyanti PR, Zimberlin CD, Bots M, Vermeulen L, Melo FS and Medema JP: Regulation of stem cell self-renewal and differentiation by Wnt and Notch are conserved throughout the adenoma-carcinoma sequence in the colon. Mol Cancer. 12:1262013. View Article : Google Scholar : PubMed/NCBI

5 

Reedijk M, Odorcic S, Zhang H, Chetty R, Tennert C, Dickson BC, Lockwood G, Gallinger S and Egan SE: Activation of Notch signaling in human colon adenocarcinoma. Int J Oncol. 33:1223–1229. 2008.PubMed/NCBI

6 

Zhang Y, Li B, Ji ZZ and Zheng PS: Notch1 regulates the growth of human colon cancers. Cancer. 116:5207–5218. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Mumm JS and Kopan R: Notch signaling: from the outside in. Dev Biol. 228:151–165. 2000. View Article : Google Scholar : PubMed/NCBI

8 

Li JL and Harris AL: Notch signaling from tumor cells: a new mechanism of angiogenesis. Cancer Cell. 8:1–3. 2005. View Article : Google Scholar : PubMed/NCBI

9 

Iso T, Kedes L and Hamamori Y: HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol. 194:237–255. 2003. View Article : Google Scholar : PubMed/NCBI

10 

Bhanot U, Köhntop R, Hasel C and Möller P: Evidence of Notch pathway activation in the ectatic ducts of chronic pancreatitis. J Pathol. 214:312–319. 2008. View Article : Google Scholar

11 

Ehebauer M, Hayward P and Arias AM: Notch, a universal arbiter of cell fate decisions. Science. 314:1414–1415. 2006. View Article : Google Scholar : PubMed/NCBI

12 

Garin JP, Despeignes J and Billerau M: Present treatment of taeniasis with niclosamide. Lyon Med. 212:1581–1588. 1964.In French. PubMed/NCBI

13 

Jin Y, Lu Z, Ding K, Li J, Du X, Chen C, Sun X, Wu Y, Zhou J and Pan J: Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: inactivation of the NF-kappaB pathway and generation of reactive oxygen species. Cancer Res. 70:2516–2527. 2010. View Article : Google Scholar : PubMed/NCBI

14 

Sack U, Walther W, Scudiero D, Selby M, Kobelt D, Lemm M, Fichtner I, Schlag PM, Shoemaker RH and Stein U: Novel effect of antihelminthic niclosamide on S100A4-mediated metastatic progression in colon cancer. J Natl Cancer Inst. 103:1018–1036. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Wieland A, Trageser D, Gogolok S, Reinartz R, Höfer H, Keller M, Leinhaas A, Schelle R, Normann S, Klaas L, et al: Anticancer effects of niclosamide in human glioblastoma. Clin Cancer Res. 19:4124–4136. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Ye T, Xiong Y, Yan Y, Xia Y, Song X, Liu L, Li D, Wang N, Zhang L and Zhu Y: et al The anthelmintic drug niclosamide induces apoptosis, impairs metastasis and reduces immunosuppressive cells in breast cancer model. PLoS One. 9:e858872014. View Article : Google Scholar : PubMed/NCBI

17 

Wang Z, Li Y, Kong D, Ahmad A, Banerjee S and Sarkar FH: Cross-talk between miRNA and Notch signaling pathways in tumor development and progression. Cancer Lett. 292:141–148. 2010. View Article : Google Scholar

18 

Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI

19 

Denli AM, Tops BB, Plasterk RH, Ketting RF and Hannon GJ: Processing of primary microRNAs by the Microprocessor complex. Nature. 432:231–235. 2004. View Article : Google Scholar : PubMed/NCBI

20 

Prokopi M, Kousparou CA and Epenetos AA: The secret role of microRNAs in cancer stem cell development and potential therapy: a Notch-pathway approach. Front Oncol. 4:3892015. View Article : Google Scholar : PubMed/NCBI

21 

Srinivasan S, Selvan ST, Archunan G, Gulyas B and Padmanabhan P: MicroRNAs -the next generation therapeutic targets in human diseases. Theranostics. 3:930–942. 2013. View Article : Google Scholar

22 

Esquela-Kerscher A and Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar : PubMed/NCBI

23 

Korpal M and Kang Y: The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis. RNA Biol. 5:115–119. 2008. View Article : Google Scholar

24 

Brabletz S, Bajdak K, Meidhof S, Burk U, Niedermann G, Firat E, Wellner U, Dimmler A, Faller G, Schubert J and Brabletz T: The ZEB1/miR-200 feedback loop controls Notch signalling in cancer cells. EMBO J. 30:770–782. 2011. View Article : Google Scholar : PubMed/NCBI

25 

Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S and Brabletz T: A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 9:582–589. 2008. View Article : Google Scholar : PubMed/NCBI

26 

Vallejo DM, Caparros E and Dominguez M: Targeting Notch signalling by the conserved miR-8/200 microRNA family in development and cancer cells. EMBO J. 30:756–769. 2011. View Article : Google Scholar : PubMed/NCBI

27 

Wang Z, Banerjee S, Ahmad A, Li Y, Azmi AS, Gunn JR, Kong D, Bao B, Ali S, Gao J, et al: Activated K-ras and INK4a/Arf deficiency cooperate during the development of pancreatic cancer by activation of Notch and NF-κB signaling pathways. PLoS One. 6:e205372011. View Article : Google Scholar

28 

Ferrari-Toninelli G, Bonini SA, Uberti D, Buizza L, Bettinsoli P, Poliani PL, Facchetti F and Memo M: Targeting Notch pathway induces growth inhibition and differentiation of neuroblastoma cells. Neuro Oncol. 12:1231–1243. 2010.PubMed/NCBI

29 

Rasul S, Balasubramanian R, Filipović A, Slade MJ, Yagüe E and Coombes RC: Inhibition of gamma-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells. Br J Cancer. 100:1879–1888. 2009. View Article : Google Scholar : PubMed/NCBI

30 

Senfter D, Holzner S, Kalipciyan M, Staribacher A, Walzl A, Huttary N, Krieger S, Brenner S, Jäger W, Krupitza G, et al: Loss of miR-200 family in 5-fluorouracil resistant colon cancer drives lymphendothelial invasiveness in vitro. Hum Mol Genet. 24:3689–3698. 2015.PubMed/NCBI

31 

Li Y, Li PK, Roberts MJ, Arend RC, Samant RS and Buchsbaum DJ: Multi-targeted therapy of cancer by niclosamide: a new application for an old drug. Cancer Lett. 349:8–14. 2014. View Article : Google Scholar : PubMed/NCBI

32 

Pastò A, Serafin V, Pilotto G, Lago C, Bellio C, Trusolino L, Bertotti A, Hoey T, Plateroti M, Esposito G, et al: NOTCH3 signaling regulates MUSASHI-1 expression in metastatic colorectal cancer cells. Cancer Res. 74:2106–2118. 2014. View Article : Google Scholar : PubMed/NCBI

33 

Ranganathan P, Weaver KL and Capobianco AJ: Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer. 11:338–351. 2011. View Article : Google Scholar : PubMed/NCBI

34 

Dai Y, Wilson G, Huang B, Peng M, Teng G, Zhang D, Zhang R, Ebert MP, Chen J, Wong BC, et al: Silencing of Jagged1 inhibits cell growth and invasion in colorectal cancer. Cell Death Dis. 5:e11702014. View Article : Google Scholar : PubMed/NCBI

35 

Ozawa T, Kazama S, Akiyoshi T, Murono K, Yoneyama S, Tanaka T, Tanaka J, Kiyomatsu T, Kawai K, Nozawa H, et al: Nuclear Notch3 expression is associated with tumor recurrence in patients with stage II and III colorectal cancer. Ann Surg Oncol. 21:2650–2658. 2014. View Article : Google Scholar : PubMed/NCBI

36 

Shih IeM and Wang TL: Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res. 67:1879–1882. 2007. View Article : Google Scholar : PubMed/NCBI

37 

Balgi AD, Fonseca BD, Donohue E, Tsang TC, Lajoie P, Proud CG, Nabi IR and Roberge M: Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling. PLoS One. 4:e71242009. View Article : Google Scholar : PubMed/NCBI

38 

Osada T, Chen M, Yang XY, Spasojevic I, Vandeusen JB, Hsu D, Clary BM, Clay TM, Chen W, Morse MA and Lyerly HK: Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations. Cancer Res. 71:4172–4182. 2011. View Article : Google Scholar : PubMed/NCBI

39 

Wang AM, Ku HH, Liang YC, Chen YC, Hwu YM and Yeh TS: The autonomous notch signal pathway is activated by baicalin and baicalein but is suppressed by niclosamide in K562 cells. J Cell Biochem. 106:682–692. 2009. View Article : Google Scholar : PubMed/NCBI

40 

Fernández-Majada V, Aguilera C, Villanueva A, Vilardell F, Robert-Moreno A, Aytés A, Real FX, Capella G, Mayo MW, Espinosa L and Bigas A: Nuclear IKK activity leads to dysregulated notch-dependent gene expression in colorectal cancer. Proc Natl Acad Sci USA. 104:276–281. 2007. View Article : Google Scholar :

41 

Qiao L and Wong BC: Role of Notch signaling in colorectal cancer. Carcinogenesis. 30:1979–1986. 2009. View Article : Google Scholar : PubMed/NCBI

42 

Jones KB, Salah Z, Del Mare S, Galasso M, Gaudio E, Nuovo GJ, Lovat F, LeBlanc K, Palatini J, Randall RL, et al: miRNA signatures associate with pathogenesis and progression of osteosarcoma. Cancer Res. 72:1865–1877. 2012. View Article : Google Scholar : PubMed/NCBI

43 

Kobayashi E, Hornicek FJ and Duan Z: MicroRNA involvement in osteosarcoma. Sarcoma. 2012:3597392012. View Article : Google Scholar : PubMed/NCBI

44 

Kong D, Li Y, Wang Z, Banerjee S, Ahmad A, Kim HR and Sarkar FH: miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells. Stem Cells. 27:1712–1721. 2009. View Article : Google Scholar : PubMed/NCBI

45 

Li Y, VandenBoom TG II, Kong D, Wang Z, Ali S, Philip PA and Sarkar FH: Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res. 69:6704–6712. 2009. View Article : Google Scholar : PubMed/NCBI

46 

Zhang B, Pan X, Cobb GP and Anderson TA: microRNAs as oncogenes and tumor suppressors. Dev Biol. 302:1–12. 2007. View Article : Google Scholar

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September 2016
Volume 38 Issue 3

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Copy and paste a formatted citation
APA
Suliman, M.A., Zhang, Z., Na, H., Ribeiro, A.L., Zhang, Y., Niang, B. ... Zuo, Y. (2016). Niclosamide inhibits colon cancer progression through downregulation of the Notch pathway and upregulation of the tumor suppressor miR-200 family. International Journal of Molecular Medicine, 38, 776-784. https://doi.org/10.3892/ijmm.2016.2689
MLA
Suliman, M. A., Zhang, Z., Na, H., Ribeiro, A. L., Zhang, Y., Niang, B., Hamid, A. S., Zhang, H., Xu, L., Zuo, Y."Niclosamide inhibits colon cancer progression through downregulation of the Notch pathway and upregulation of the tumor suppressor miR-200 family". International Journal of Molecular Medicine 38.3 (2016): 776-784.
Chicago
Suliman, M. A., Zhang, Z., Na, H., Ribeiro, A. L., Zhang, Y., Niang, B., Hamid, A. S., Zhang, H., Xu, L., Zuo, Y."Niclosamide inhibits colon cancer progression through downregulation of the Notch pathway and upregulation of the tumor suppressor miR-200 family". International Journal of Molecular Medicine 38, no. 3 (2016): 776-784. https://doi.org/10.3892/ijmm.2016.2689