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Effect of the Wnt/β-catenin pathway inhibitors on cell proliferation and migration of HEC-1A endometrial adenocarcinoma: experimental cell culture model

Yıl 2021, Cilt: 7 Sayı: 3, 218 - 224, 04.05.2021
https://doi.org/10.18621/eurj.900847

Öz

Objectives: The most diagnosed tumor among infiltrating tumors of the female genital tract is endometrial carcinoma. The Wnt/β-catenin signaling pathway has an important role in organogenesis, self-renewal of tissues, and adult stem cell maintenance. However aberrant activation of it causes many types of tumors and also related to the prognosis of patients. Therefore, we aimed to investigate whether Wnt/β-catenin pathway inhibitors have any effect on the proliferation and migration of tumor cells.


Methods:
As cancer cell line, HEC-1A endometrial adenocarcinoma was used. The Wnt/β-catenin pathway inhibitors effects on proliferation and migration were demonstrated by real-time cell analysis device and wound healing model respectively.


Results:
Wnt/β-catenin pathway inhibitors FH535 (25 μM at 36th hour, p < 0.05; 50μM at 48th hour p < 0.001) and niclosamide inhibited cell proliferation (10, 25 and 50μM at 60th hours; p < 0.01, p < 0.05 and p < 0.001, respectively) whereas ICRT14 and IWP-2 did not. However only niclosamide which is also an antihelmintic drug inhibited migration of the cells in all concentrations tested (10, 25 and 50μM, p < 0.05).

Conclusions: The present study shows that the Wnt/β-catenin pathway has an substantial role in both proliferation and migration of endometrial adenocarcinoma. We suggest that the antihelmintic drug niclosamide could be further investigated for its potential therapeutic effect in endometrial adenocarcinoma.

Destekleyen Kurum

Mersin University Scientific Research Projects Center

Proje Numarası

2018-2-TP2-3022

Kaynakça

  • 1. Pillozzi S, Fortunato A, Lorenzo ED, Borrani E, Giachi M, Scarselli G, et al. Over-expression of the LH receptor increases distant metastases in an endometrial cancer mouse model. Front Oncol 2013;3:285.
  • 2. Antovska VS, Krstevska I, Trajanova M, Chelebieva J, Gosheva I, Zdravkovski P, et al. Endometrioid Adenocarcinoma Arising in Adenomyoma in a Woman with a Genital Prolapse-Case Report. Open Access Maced J Med Sci 2018;14:1091-4.
  • 3. Morice P, Leary A, Creutzberg C, Abu-Rustum N, Darai E. Endometrial cancer. Lancet 2016;12:1094-1108.
  • 4. Mac Donald BT, Tamai K, He X. Wnt/b-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009;17:9-26.
  • 5. White BD, Chien AJ, Dawson DW. Dysregulation of Wnt/b-catenin signaling in gastrointestinal cancers. Gastroenterology 2012;142:219-32.
  • 6. Kobayashi K, Sagae S, Nishioka Y, Tokino T, Kudo R. Mutations of the beta catenin gene in endometrial carcinomas. Jpn J Cancer Res 1999;90:55-9.
  • 7. Fukuchi T, Sakamoto M, Tsuda H, Maruyama K, Nozawa S, Hirohashi S. Beta-catenin mutation in carcinoma of the uterine endometrium. Cancer Res 1998;58:3526-28.
  • 8. Saegusa M, Hashimura M, Yoshida T, Okayasu I. beta- Catenin mutations and aberrant nuclear expression during endometrial tumorigenesis. Br J Cancer 2001;84:209-17.
  • 9. Wang Y, van der Zee M, Fodde R, Blok LJ. Wnt/Β-catenin and sex hormone signaling in endometrial homeostasis and cancer. Oncotarget 2010;1:674-84.
  • 10. Polakis P. Wnt signaling in cancer. Cold Spring Harb Perspect Biol 2012;4:a008052.
  • 11. Matsuzaki S, Darcha C. In vitro effects of a small-molecule antagonist of the Tcf/sscatenin complex on endometrial and endometriotic cells of patients with endometriosis. PLoS One. 2013;8:e61690.
  • 12. Hevir-Kene N, Rižner TL. The endometrial cancer cell lines Ishikawa and HEC-1A, and the control cell line HIEEC, differ in expression of estrogen biosynthetic and metabolic genes, and in androstenedione and estrone-sulfate metabolism. Chem Biol Interact 2015;234:309-19.
  • 13. Handeli S, Simon JA. A small-molecule inhibitor of Tcf/beta-catenin signaling down-regulates PPARgamma and PPARdelta activities. Mol Cancer Ther 2008;7:521-9.
  • 14. Tomizawa M, Shinozaki F, Hasegawa R, Shirai Y, Motoyoshi Y, Sugiyama T, et al. Immunosuppressive agents are associated with peptic ulcer bleeding. Exp Ther Med 2017;13:1927-31.
  • 15. Chen Y, Rao X, Huang K, Jiang X, Wang H, Teng L. FH535 Inhibits proliferation and motility of colon cancer cells by targeting Wnt/β-catenin signaling pathway. J Cancer 2017;8:3142-53.
  • 16. Wu MY, Liang RR, Chen K, Shen M, Tian YL, Li DM, et al. FH535 inhibited metastasis and growth of pancreatic cancer cells. Onco Targets Ther 2015;8:1651-70.
  • 17. Gustafson CT, Mamo T, Shogren KL, Maran A, Yaszemski MJ. FH535 Suppresses Osteosarcoma Growth In Vitro and Inhibits Wnt Signaling through Tankyrases. Front Pharmacol 2017;8:285.
  • 18. Li Y, Li PK, Roberts MJ, Arend RC, Samant RS, Buchsbaum DJ. Multi-targeted therapy of cancer by niclosamide: a new application for an old drug. Cancer Letters 2014;349:8-14.
  • 19. Gyamfi J, Lee YH, Min BS, Choi J. Niclosamide reverses adipocyte induced epithelial-mesenchymal transition in breast cancer cells via suppression of the interleukin-6/STAT3 signalling axis. Sci Rep 2019;9:11336.
  • 20. Arend RC, Londoño-Joshi AI, Gangrade A, Katre AA, Kurpad C, Li Y, et al. Niclosamide and its analogs are potent inhibitors of Wnt/β-catenin, mTOR and STAT3 signaling in ovarian cancer. Oncotarget 2016;7:86803-15.
  • 21. Zhao J, He Q, Gong Z, Chen S, Cui L. Niclosamide suppresses renal cell carcinoma by inhibiting Wnt/β-catenin and inducing mitochondrial dysfunctions. Springerplus 2016;5:1436.
  • 22. Wang C, Zhou X, Xu H, Shi X, Zhao J, Yang M, et al. Niclosamide inhibits cell growth and enhances drug sensitivity of hepatocellular carcinoma cells via STAT3 signaling pathway. J Cancer 2018;9:4150-55.
  • 23. Liu C, Lou W, Armstrong C, Zhu Y, Evans CP, Gao AC. Niclosamide suppresses cell migration and invasion in enzalutamide resistant prostate cancer cells via Stat3-AR axis inhibition. Prostate 2015;75:1341-53.
  • 24. Li Z, Yu Y, Sun S, Qi B, Wang W, Yu A. Niclosamide inhibits the proliferation of human osteosarcoma cell lines by inducing apoptosis and cell cycle arrest. Oncol Rep 2015;3:1763-8.
  • 25. Gonsalves FC, Klein K, Carson BB, Katz S, Ekas LA, Evans S. An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway. Proc Natl Acad Sci U S A 2011;108:5954-63.
  • 26. Dandekar S, Romanos-Sirakis E, Pais F, Bhatla T, Jones C, Bourgeois W, et al. Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia. Br J Haematol 2014;167:87-99.
  • 27. García-Reyes B, Witt L, Jansen B, Karasu E, Gehring T, Leban J, et al. Discovery of inhibitor of Wnt production 2 (IWP-2) and related compounds as selective ATP-competitive inhibitors of casein kinase 1 (CK1) δ/ε. J Med Chem 2018;61:4087-102. .
  • 28. Kleszcz R, Szymańska A, Krajka-Kuźniak V, Baer-Dubowska W, Paluszczak J. Inhibition of CBP/β-catenin and porcupine attenuates Wnt signaling and induces apoptosis in head and neck carcinoma cells. Cell Oncol (Dordr) 2019;42:505-20.
  • 29. Tong Y, Liu Y, Zheng H, Zheng L, Liu W, Wu J, et al. Artemisinin and its derivatives can significantly inhibit lung tumorigenesis and tumor metastasis through Wnt/β-catenin signaling. Oncotarget 2016;7:31413-28.
Yıl 2021, Cilt: 7 Sayı: 3, 218 - 224, 04.05.2021
https://doi.org/10.18621/eurj.900847

Öz

Proje Numarası

2018-2-TP2-3022

Kaynakça

  • 1. Pillozzi S, Fortunato A, Lorenzo ED, Borrani E, Giachi M, Scarselli G, et al. Over-expression of the LH receptor increases distant metastases in an endometrial cancer mouse model. Front Oncol 2013;3:285.
  • 2. Antovska VS, Krstevska I, Trajanova M, Chelebieva J, Gosheva I, Zdravkovski P, et al. Endometrioid Adenocarcinoma Arising in Adenomyoma in a Woman with a Genital Prolapse-Case Report. Open Access Maced J Med Sci 2018;14:1091-4.
  • 3. Morice P, Leary A, Creutzberg C, Abu-Rustum N, Darai E. Endometrial cancer. Lancet 2016;12:1094-1108.
  • 4. Mac Donald BT, Tamai K, He X. Wnt/b-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009;17:9-26.
  • 5. White BD, Chien AJ, Dawson DW. Dysregulation of Wnt/b-catenin signaling in gastrointestinal cancers. Gastroenterology 2012;142:219-32.
  • 6. Kobayashi K, Sagae S, Nishioka Y, Tokino T, Kudo R. Mutations of the beta catenin gene in endometrial carcinomas. Jpn J Cancer Res 1999;90:55-9.
  • 7. Fukuchi T, Sakamoto M, Tsuda H, Maruyama K, Nozawa S, Hirohashi S. Beta-catenin mutation in carcinoma of the uterine endometrium. Cancer Res 1998;58:3526-28.
  • 8. Saegusa M, Hashimura M, Yoshida T, Okayasu I. beta- Catenin mutations and aberrant nuclear expression during endometrial tumorigenesis. Br J Cancer 2001;84:209-17.
  • 9. Wang Y, van der Zee M, Fodde R, Blok LJ. Wnt/Β-catenin and sex hormone signaling in endometrial homeostasis and cancer. Oncotarget 2010;1:674-84.
  • 10. Polakis P. Wnt signaling in cancer. Cold Spring Harb Perspect Biol 2012;4:a008052.
  • 11. Matsuzaki S, Darcha C. In vitro effects of a small-molecule antagonist of the Tcf/sscatenin complex on endometrial and endometriotic cells of patients with endometriosis. PLoS One. 2013;8:e61690.
  • 12. Hevir-Kene N, Rižner TL. The endometrial cancer cell lines Ishikawa and HEC-1A, and the control cell line HIEEC, differ in expression of estrogen biosynthetic and metabolic genes, and in androstenedione and estrone-sulfate metabolism. Chem Biol Interact 2015;234:309-19.
  • 13. Handeli S, Simon JA. A small-molecule inhibitor of Tcf/beta-catenin signaling down-regulates PPARgamma and PPARdelta activities. Mol Cancer Ther 2008;7:521-9.
  • 14. Tomizawa M, Shinozaki F, Hasegawa R, Shirai Y, Motoyoshi Y, Sugiyama T, et al. Immunosuppressive agents are associated with peptic ulcer bleeding. Exp Ther Med 2017;13:1927-31.
  • 15. Chen Y, Rao X, Huang K, Jiang X, Wang H, Teng L. FH535 Inhibits proliferation and motility of colon cancer cells by targeting Wnt/β-catenin signaling pathway. J Cancer 2017;8:3142-53.
  • 16. Wu MY, Liang RR, Chen K, Shen M, Tian YL, Li DM, et al. FH535 inhibited metastasis and growth of pancreatic cancer cells. Onco Targets Ther 2015;8:1651-70.
  • 17. Gustafson CT, Mamo T, Shogren KL, Maran A, Yaszemski MJ. FH535 Suppresses Osteosarcoma Growth In Vitro and Inhibits Wnt Signaling through Tankyrases. Front Pharmacol 2017;8:285.
  • 18. Li Y, Li PK, Roberts MJ, Arend RC, Samant RS, Buchsbaum DJ. Multi-targeted therapy of cancer by niclosamide: a new application for an old drug. Cancer Letters 2014;349:8-14.
  • 19. Gyamfi J, Lee YH, Min BS, Choi J. Niclosamide reverses adipocyte induced epithelial-mesenchymal transition in breast cancer cells via suppression of the interleukin-6/STAT3 signalling axis. Sci Rep 2019;9:11336.
  • 20. Arend RC, Londoño-Joshi AI, Gangrade A, Katre AA, Kurpad C, Li Y, et al. Niclosamide and its analogs are potent inhibitors of Wnt/β-catenin, mTOR and STAT3 signaling in ovarian cancer. Oncotarget 2016;7:86803-15.
  • 21. Zhao J, He Q, Gong Z, Chen S, Cui L. Niclosamide suppresses renal cell carcinoma by inhibiting Wnt/β-catenin and inducing mitochondrial dysfunctions. Springerplus 2016;5:1436.
  • 22. Wang C, Zhou X, Xu H, Shi X, Zhao J, Yang M, et al. Niclosamide inhibits cell growth and enhances drug sensitivity of hepatocellular carcinoma cells via STAT3 signaling pathway. J Cancer 2018;9:4150-55.
  • 23. Liu C, Lou W, Armstrong C, Zhu Y, Evans CP, Gao AC. Niclosamide suppresses cell migration and invasion in enzalutamide resistant prostate cancer cells via Stat3-AR axis inhibition. Prostate 2015;75:1341-53.
  • 24. Li Z, Yu Y, Sun S, Qi B, Wang W, Yu A. Niclosamide inhibits the proliferation of human osteosarcoma cell lines by inducing apoptosis and cell cycle arrest. Oncol Rep 2015;3:1763-8.
  • 25. Gonsalves FC, Klein K, Carson BB, Katz S, Ekas LA, Evans S. An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway. Proc Natl Acad Sci U S A 2011;108:5954-63.
  • 26. Dandekar S, Romanos-Sirakis E, Pais F, Bhatla T, Jones C, Bourgeois W, et al. Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia. Br J Haematol 2014;167:87-99.
  • 27. García-Reyes B, Witt L, Jansen B, Karasu E, Gehring T, Leban J, et al. Discovery of inhibitor of Wnt production 2 (IWP-2) and related compounds as selective ATP-competitive inhibitors of casein kinase 1 (CK1) δ/ε. J Med Chem 2018;61:4087-102. .
  • 28. Kleszcz R, Szymańska A, Krajka-Kuźniak V, Baer-Dubowska W, Paluszczak J. Inhibition of CBP/β-catenin and porcupine attenuates Wnt signaling and induces apoptosis in head and neck carcinoma cells. Cell Oncol (Dordr) 2019;42:505-20.
  • 29. Tong Y, Liu Y, Zheng H, Zheng L, Liu W, Wu J, et al. Artemisinin and its derivatives can significantly inhibit lung tumorigenesis and tumor metastasis through Wnt/β-catenin signaling. Oncotarget 2016;7:31413-28.
Toplam 29 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Klinik Tıp Bilimleri
Bölüm Original Article
Yazarlar

Yaşam Çirçirci Bu kişi benim 0000-0003-0283-6955

R. Nalan Tiftik 0000-0001-7277-3369

İsmail Ün 0000-0001-6442-4185

Proje Numarası 2018-2-TP2-3022
Yayımlanma Tarihi 4 Mayıs 2021
Gönderilme Tarihi 22 Mart 2021
Kabul Tarihi 29 Mart 2021
Yayımlandığı Sayı Yıl 2021 Cilt: 7 Sayı: 3

Kaynak Göster

AMA Çirçirci Y, Tiftik RN, Ün İ. Effect of the Wnt/β-catenin pathway inhibitors on cell proliferation and migration of HEC-1A endometrial adenocarcinoma: experimental cell culture model. Eur Res J. Mayıs 2021;7(3):218-224. doi:10.18621/eurj.900847

e-ISSN: 2149-3189 


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