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International Journal of Molecular Medicine
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Article

Differential effects of tetrahydropyridinol derivatives on β-catenin signaling and invasion in human hepatocellular and breast carcinoma cells

  • Authors:
    • Anandam Kasin Yadunandam
    • Jin-Soo Yoon
    • Yeon Tae Jeong
    • Woe-Yeon Kim
    • Sang-Yeol Lee
    • Gun-Do Kim
  • View Affiliations / Copyright

    Affiliations: Department of Microbiology, College of Natural Sciences, Pukyong National University, Busan 608-737, Republic of Korea, Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australia, Department of Image Science and Engineering, College of Engineering, Pukyong National University, Busan 608-737, Republic of Korea, Division of Applied Life Science, Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, Jinju 660-701, Republic of Korea
  • Pages: 577-587
    |
    Published online on: June 9, 2015
       https://doi.org/10.3892/ijmm.2015.2240
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Abstract

In continuation of previous efforts to investigate the biological potency of tetrahydropyridinol derivatives, the present study synthesized three target compounds: N-(bromoacetyl)-3-carboxyethyl-2,6-diphenyl-4-O-(pentafluorobenzoyl)-Δ3-tetra-hydropyridine (5a), N-(chloroacetyl)-3-carboxyethyl-2,6-diphenyl-4-O-(pentafluorobenzoyl)-Δ3-tetrahydropyridine (5b) and N-(2-bromopropanoyl)-3-carboxyethyl-2,6-diphenyl-4-O-(pentafluorobenzoyl)-Δ3-tetrahydropyridine (5c), and examined their anticancer potency. Experiments were performed using the Sk-Hep1 and Hep3B human hepatocellular carcinoma cell lines and MDA-MB-231 breast adenocarcinoma cell line. Among the three compounds, 5a and 5b were comparably and significantly cytotoxic to the Sk-Hep1, Hep3B and MDA-MB-231 cells. The highest level of cytotoxicity was detected in theSk-Hep1 cells with half maximal inhibitory concentrations for compounds 5a and 5b at 12 and 6 µM, respectively. These two compounds induced cell cycle arrest in the Sk-Hep1 and MDA-MB-231 cells through the downregulation of β-catenin and upregulation of glycogen synthase kinase-3β and E-cadherin. By contrast, 5a and 5b induced G1 arrest in the Hep3B cells by modulating the p21 and p27 cell cycle regulatory molecules and cyclin-dependent kinase 2. In addition, 5a and 5b significantly inhibited the invasion of Sk-Hep1 and MDA-MB-231 cells. These results suggested that the 5a and 5b compounds induce cell cycle arrest by suppressing Wnt/β-catenin signaling in highly invasive Sk-Hep1 and MDA-MB-231 cells, and by inducing p53 independent cell cycle arrest in Hep3B cells.
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1 

Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI

2 

Ries L, Melbert D, Krapcho M, Stinchcomb D, Howlader N, Horner M, Mariotto A, Miller B, Feuer E and Altekruse S: SEER Cancer Statistics Review. Based on November 2007 SEER data submission, posted to the SEER web site. National Cancer Institute; Bethesda, MD: 2008

3 

Roayaie S, Blume IN, Thung SN, Guido M, Fiel MI, Hiotis S, Labow DM, Llovet JM and Schwartz ME: A system of classifying microvascular invasion to predict outcome after resection in patients with hepatocellular carcinoma. Gastroenterology. 137:850–855. 2009. View Article : Google Scholar : PubMed/NCBI

4 

Lang L: FDA approves sorafenib for patients with inoperable liver cancer. Gastroenterology. 134:3792008.PubMed/NCBI

5 

Clevers H: Wnt/beta-catenin signaling in development and disease. Cell. 127:469–480. 2006. View Article : Google Scholar : PubMed/NCBI

6 

Cadigan KM: Wnt-β-catenin signaling. Curr Biol. 18:R943–R947. 2008. View Article : Google Scholar : PubMed/NCBI

7 

Kemler R: From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet. 9:317–321. 1993. View Article : Google Scholar : PubMed/NCBI

8 

Jamora C and Fuchs E: Intercellular adhesion, signalling and the cytoskeleton. Nat Cell Biol. 4:E101–E108. 2002. View Article : Google Scholar : PubMed/NCBI

9 

Clevers H: Wnt/β-catenin signaling in development and disease. Cell. 127:469–480. 2006. View Article : Google Scholar : PubMed/NCBI

10 

Polakis P: The many ways of Wnt in cancer. Curr Opin Genet Dev. 17:45–51. 2007. View Article : Google Scholar : PubMed/NCBI

11 

Zucman-Rossi J, Benhamouche S, Godard C, Boyault S, Grimber G, Balabaud C, Cunha A, Bioulac-Sage P and Perret C: Differential effects of inactivated Axin1 and activated β-catenin mutations in human hepatocellular carcinomas. Oncogene. 26:774–780. 2007. View Article : Google Scholar

12 

Fujie H, Moriya K, Shintani Y, Tsutsumi T, Takayama T, Makuuchi M, Kimura S and Koike K: Frequent beta-catenin aberration in human hepatocellular carcinoma. Hepatol Res. 20:39–51. 2001. View Article : Google Scholar : PubMed/NCBI

13 

Kim YD, Park CH, Kim HS, Choi SK, Rew JS, Kim DY, Koh YS, Jeung KW, Lee KH and Lee JS: Genetic alterations of Wnt signaling pathway-associated genes in hepatocellular carcinoma. J Gastroenterol Hepatol. 23:110–118. 2008. View Article : Google Scholar : PubMed/NCBI

14 

Laurent-Puig P and Zucman-Rossi J: Genetics of hepatocellular tumors. Oncogene. 25:3778–3786. 2006. View Article : Google Scholar : PubMed/NCBI

15 

Aridoss G, Amirthaganesan S, Kumar NA, Kim JT, Lim KT, Kabilan S and Jeong YT: A facile synthesis, antibacterial, and antitubercular studies of some piperidin-4-one and tetrahydro-pyridine derivatives. Bioorg Med Chem Lett. 18:6542–6548. 2008. View Article : Google Scholar : PubMed/NCBI

16 

Aridoss G, Amirthaganesan S and Jeong YT: Synthesis, crystal and antibacterial studies of diversely functionalized tetrahy-dropyridin-4-ol. Bioorg Med Chem Lett. 20:2242–2249. 2010. View Article : Google Scholar : PubMed/NCBI

17 

Awasthi N, Schwarz MA, Verma V, Cappiello C and Schwarz RE: Endothelial monocyte activating polypeptide II interferes with VEGF-induced proangiogenic signaling. Lab Invest. 89:38–46. 2009. View Article : Google Scholar

18 

Hung WC and Chang HC: Indole-3-carbinol inhibits Sp1-induced matrix metalloproteinase-2 expression to attenuate migration and invasion of breast cancer cells. J Agric Food Chem. 57:76–82. 2009. View Article : Google Scholar

19 

Pai R, Tarnawski AS and Tran T: Deoxycholic acid activates β-catenin signaling pathway and increases colon cell cancer growth and invasiveness. Mol Biol Cell. 15:2156–2163. 2004. View Article : Google Scholar : PubMed/NCBI

20 

MacDonald BT, Tamai K and He X: Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev Cell. 17:9–26. 2009. View Article : Google Scholar : PubMed/NCBI

21 

Tetsu O and McCormick F: β-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 398:422–426. 1999. View Article : Google Scholar : PubMed/NCBI

22 

He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B and Kinzler KW: Identification of c-MYC as a target of the APC pathway. Science. 281:1509–1512. 1998. View Article : Google Scholar : PubMed/NCBI

23 

Wei Y, Van Nhieu JT, Prigent S, Srivatanakul P, Tiollais P and Buendia MA: Altered expression of E-cadherin in hepa-tocellular carcinoma: correlations with genetic alterations, β-catenin expression, and clinical features. Hepatology. 36:692–701. 2002. View Article : Google Scholar : PubMed/NCBI

24 

Matsumura T, Makino R and Mitamura K: Frequent down-regulation of E-cadherin by genetic and epigenetic changes in the malignant progression of hepatocellular carcinomas. Clin Cancer Res. 7:594–599. 2001.PubMed/NCBI

25 

Sakanaka C, Weiss JB and Williams LT: Bridging of β-catenin and glycogen synthase kinase-3β by axin and inhibition of β-catenin-mediated transcription. Proc Natl Acad Sci USA. 95:3020–3023. 1998. View Article : Google Scholar

26 

Acs G, Lawton TJ, Rebbeck TR, LiVolsi VA and Zhang PJ: Differential expression of E-cadherin in lobular and ductal neoplasms of the breast and its biologic and diagnostic implications. Am J Clin Pathol. 115:85–98. 2001. View Article : Google Scholar : PubMed/NCBI

27 

Rakha EA, Patel A, Powe DG, et al: Clinical and biological significance of E-cadherin protein expression in invasive lobular carcinoma of the breast. Am J Surg Pathol. 34:1472–1479. 2010. View Article : Google Scholar : PubMed/NCBI

28 

Gould Rothberg BE and Bracken MB: E-cadherin immunohisto-chemical expression as a prognostic factor in infiltrating ductal carcinoma of the breast: a systematic review and meta-analysis. Breast Cancer Res Thr. 100:139–148. 2006. View Article : Google Scholar

29 

Orsulic S, Huber O, Aberle H, Arnold S and Kemler R: E-cadherin binding prevents beta-catenin nuclear localization and beta-catenin/LEF-1-mediated transactivation. J Cell Sci. 112:1237–1245. 1999.PubMed/NCBI

30 

Harper JW and Elledge SJ: Cdk inhibitors in development and cancer. Curr Opin Genet Dev. 6:56–64. 1996. View Article : Google Scholar : PubMed/NCBI

31 

Yew PR: Ubiquitin-mediated proteolysis of vertebrate G1- and S-phase regulators. J Cell Physiol. 187:1–10. 2001. View Article : Google Scholar : PubMed/NCBI

32 

Zeng YX and el-Deiry WS: Regulation of p21WAF1/CIP1 expression by p53-independent pathways. Oncogene. 12:1557–1564. 1996.PubMed/NCBI

33 

Brandi G, Paiardini M, Cervasi B, Fiorucci C, Filippone P, De Marco C, Zaffaroni N and Magnani M: A new indole-3-carbinol tetrameric derivative inhibits cyclin-dependent kinase 6 expression, and induces G1 cell cycle arrest in both estrogen-dependent and estrogen-independent breast cancer cell lines. Cancer Res. 63:4028–4036. 2003.PubMed/NCBI

34 

Nakajima M, Welch DR, Belloni PN and Nicolson GL: Degradation of basement membrane type IV collagen and lung subendothelial matrix by rat mammary adenocarcinoma cell clones of differing metastatic potentials. Cancer Res. 47:4869–4876. 1987.PubMed/NCBI

35 

Mareel MM, Van Roy FM and De Baetselier P: The invasive phenotypes. Cancer Metastasis Rev. 9:45–62. 1990. View Article : Google Scholar : PubMed/NCBI

36 

Christofori G and Semb H: The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci. 24:73–76. 1999. View Article : Google Scholar : PubMed/NCBI

37 

Huang GJ, Yang CM, Chang YS, Amagaya S, Wang HC, Hou WC, Huang SS and Hu ML: Hispolon suppresses SK-Hep1 human hepatoma cell metastasis by inhibiting matrix metal-loproteinase-2/9 and urokinase-plasminogen activator through the PI3K/Akt and ERK signaling pathways. J Agric Food Chem. 58:9468–9475. 2010. View Article : Google Scholar : PubMed/NCBI

38 

Hwang ES and Lee HJ: Inhibitory effects of lycopene on the adhesion, invasion, and migration of SK-Hep1 human hepatoma cells. Exp Biol Med. 231:322–327. 2006.

39 

Meng Q, Qi M, Chen DZ, Yuan R, Goldberg ID, Rosen E, Auborn K and Fan S: Suppression of breast cancer invasion and migration by indole-3-carbinol: associated with up-regulation of BRCA1 and E-cadherin/catenin complexes. J Mol Med. 78:155–165. 2000. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Yadunandam AK, Yoon J, Jeong YT, Kim W, Lee S and Kim G: Differential effects of tetrahydropyridinol derivatives on β-catenin signaling and invasion in human hepatocellular and breast carcinoma cells. Int J Mol Med 36: 577-587, 2015.
APA
Yadunandam, A.K., Yoon, J., Jeong, Y.T., Kim, W., Lee, S., & Kim, G. (2015). Differential effects of tetrahydropyridinol derivatives on β-catenin signaling and invasion in human hepatocellular and breast carcinoma cells. International Journal of Molecular Medicine, 36, 577-587. https://doi.org/10.3892/ijmm.2015.2240
MLA
Yadunandam, A. K., Yoon, J., Jeong, Y. T., Kim, W., Lee, S., Kim, G."Differential effects of tetrahydropyridinol derivatives on β-catenin signaling and invasion in human hepatocellular and breast carcinoma cells". International Journal of Molecular Medicine 36.2 (2015): 577-587.
Chicago
Yadunandam, A. K., Yoon, J., Jeong, Y. T., Kim, W., Lee, S., Kim, G."Differential effects of tetrahydropyridinol derivatives on β-catenin signaling and invasion in human hepatocellular and breast carcinoma cells". International Journal of Molecular Medicine 36, no. 2 (2015): 577-587. https://doi.org/10.3892/ijmm.2015.2240
Copy and paste a formatted citation
x
Spandidos Publications style
Yadunandam AK, Yoon J, Jeong YT, Kim W, Lee S and Kim G: Differential effects of tetrahydropyridinol derivatives on β-catenin signaling and invasion in human hepatocellular and breast carcinoma cells. Int J Mol Med 36: 577-587, 2015.
APA
Yadunandam, A.K., Yoon, J., Jeong, Y.T., Kim, W., Lee, S., & Kim, G. (2015). Differential effects of tetrahydropyridinol derivatives on β-catenin signaling and invasion in human hepatocellular and breast carcinoma cells. International Journal of Molecular Medicine, 36, 577-587. https://doi.org/10.3892/ijmm.2015.2240
MLA
Yadunandam, A. K., Yoon, J., Jeong, Y. T., Kim, W., Lee, S., Kim, G."Differential effects of tetrahydropyridinol derivatives on β-catenin signaling and invasion in human hepatocellular and breast carcinoma cells". International Journal of Molecular Medicine 36.2 (2015): 577-587.
Chicago
Yadunandam, A. K., Yoon, J., Jeong, Y. T., Kim, W., Lee, S., Kim, G."Differential effects of tetrahydropyridinol derivatives on β-catenin signaling and invasion in human hepatocellular and breast carcinoma cells". International Journal of Molecular Medicine 36, no. 2 (2015): 577-587. https://doi.org/10.3892/ijmm.2015.2240
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