Advertisement

Neuraminidase 1 regulates proliferation, apoptosis and the expression of Cadherins in mammary carcinoma cells

  • Padmamalini ThulasiramanEmail author
  • Kelbie Kerr
  • Kathleen McAlister
  • Samantha Hardisty
  • Albany Wistner
  • Ian McCullough
Article

Abstract

The link between Neuraminidase 1 (Neu1) and cancer development has been highlighted in numerous studies. In an effort to understand the role of Neu1 in mammary carcinoma cells, we evaluated the effect of Neu1 on controlling cell proliferation and apoptosis, as well as regulating the expression of cadherins. By blocking the activity of Neu1 with oseltamivir phosphate or using siRNA to silence the Neu1 protein, we observed suppression of cell growth in MCF-7 and MDA-MB-231 cells. Enhanced cleaved caspase 3 expression was demonstrated in breast cancer cells treated with oseltamivir phosphate or in Neu1 knockdown mammary carcinoma cells. We also provided evidence of Neu1 reversing the epithelial-mesenchymal properties with associated changes to the respective cadherin family. Additional observations indicated that the phytochemical, honokiol downregulates the expression of Neu1. As a consequence of blocking Neu1, honokiol reduced the levels of sialic acid in the two subtypes of breast cancer. These findings provide evidence that Neu1 regulates cell growth and death, and facilitates cancer progression by modulating the expression levels of cadherins.

Keywords

Neuraminidase 1 Breast cancer Honokiol Cadherins 

Notes

Acknowledgements

This work was funded by the Interprofessional Research across the Health/Medical Sciences, University of South Alabama, Office of Research and Economic Development and the start-up funds from the College of Allied Health Professions at University of South Alabama.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    d’Azzo A, Bonten E (2010) Molecular mechanisms of pathogenesis in a glycosphingolipid and a glycoprotein storage disease. Biochem Soc Trans 38:1453–1457.  https://doi.org/10.1042/BST0381453 CrossRefGoogle Scholar
  2. 2.
    Monti E, Bonten E, D’Azzo A, Bresciani R, Venerando B, Borsani G, Schauer R, Tettamanti G (2010) Sialidases in vertebrates: a family of enzymes tailored for several cell functions. Adv Carbohydr Chem Biochem 64:403–479.  https://doi.org/10.1016/S0065-2318(10)64007-3 CrossRefGoogle Scholar
  3. 3.
    Hou G, Liu G, Yang Y, Li Y, Yuan S, Zhao L, Wu M, Liu L, Zhou W (2016) Neuraminidase 1 (NEU1) promotes proliferation and migration as a diagnostic and prognostic biomarker of hepatocellular carcinoma. Oncotarget 7:64957–64966.  https://doi.org/10.18632/oncotarget.11778 Google Scholar
  4. 4.
    O’Shea LK, Abdulkhalek S, Allison S, Neufeld RJ, Szewczuk MR (2014) Therapeutic targeting of Neu1 sialidase with oseltamivir phosphate (Tamiflu(R)) disables cancer cell survival in human pancreatic cancer with acquired chemoresistance. Onco Targets Ther 7:117–134.  https://doi.org/10.2147/OTT.S55344 Google Scholar
  5. 5.
    Ren LR, Zhang LP, Huang SY, Zhu YF, Li WJ, Fang SY, Shen L, Gao YL (2016) Effects of sialidase NEU1 siRNA on proliferation, apoptosis, and invasion in human ovarian cancer. Mol Cell Biochem 411:213–219.  https://doi.org/10.1007/s11010-015-2583-z CrossRefGoogle Scholar
  6. 6.
    Haxho F, Allison S, Alghamdi F, Brodhagen L, Kuta VE, Abdulkhalek S, Neufeld RJ, Szewczuk MR (2014) Oseltamivir phosphate monotherapy ablates tumor neovascularization, growth, and metastasis in mouse model of human triple-negative breast adenocarcinoma. Breast Cancer (Dove Med Press) 6:191–203.  https://doi.org/10.2147/BCTT.S74663 Google Scholar
  7. 7.
    Gilmour AM, Abdulkhalek S, Cheng TS, Alghamdi F, Jayanth P, O’Shea LK, Geen O, Arvizu LA, Szewczuk MR (2013) A novel epidermal growth factor receptor-signaling platform and its targeted translation in pancreatic cancer. Cell Signal 25:2587–2603.  https://doi.org/10.1016/j.cellsig.2013.08.008 CrossRefGoogle Scholar
  8. 8.
    Pearce OM, Laubli H (2016) Sialic acids in cancer biology and immunity. Glycobiology 26:111–128.  https://doi.org/10.1093/glycob/cwv097 CrossRefGoogle Scholar
  9. 9.
    Varki A (2008) Sialic acids in human health and disease. Trends Mol Med 14:351–360.  https://doi.org/10.1016/j.molmed.2008.06.002 CrossRefGoogle Scholar
  10. 10.
    Garbar C, Mascaux C, Merrouche Y, Bensussan A (2018) Triple-negative and HER2-overexpressing breast cancer cell sialylation impacts tumor microenvironment T-lymphocyte subset recruitment: a possible mechanism of tumor escape. Cancer Manag Res 10:1051–1059.  https://doi.org/10.2147/CMAR.S162932 CrossRefGoogle Scholar
  11. 11.
    Hollingsworth MA, Swanson BJ (2004) Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer 4:45–60.  https://doi.org/10.1038/nrc1251 CrossRefGoogle Scholar
  12. 12.
    Sawada T, Ho JJ, Sagabe T, Yoon WH, Chung YS, Sowa M, Kim YS (1993) Biphasic effect of cell surface sialic acids on pancreatic cancer cell adhesiveness. Biochem Biophys Res Commun 195:1096–1103.  https://doi.org/10.1006/bbrc.1993.2157 CrossRefGoogle Scholar
  13. 13.
    To H, Ohdo S, Shin M, Uchimaru H, Yukawa E, Higuchi S, Fujimura A, Kobayashi E (2003) Dosing time dependency of doxorubicin-induced cardiotoxicity and bone marrow toxicity in rats. J Pharm Pharmacol 55:803–810.  https://doi.org/10.1211/002235703765951410 CrossRefGoogle Scholar
  14. 14.
    Hu H, Zhang XX, Wang YY, Chen SZ (2005) Honokiol inhibits arterial thrombosis through endothelial cell protection and stimulation of prostacyclin. Acta Pharmacol Sin 26:1063–1068.  https://doi.org/10.1111/j.1745-7254.2005.00164.x CrossRefGoogle Scholar
  15. 15.
    Kim BH, Cho JY (2008) Anti-inflammatory effect of honokiol is mediated by PI3 K/Akt pathway suppression. Acta Pharmacol Sin 29:113–122.  https://doi.org/10.1111/j.1745-7254.2008.00725.x CrossRefGoogle Scholar
  16. 16.
    Kumar A, Kumar Singh U, Chaudhary A (2013) Honokiol analogs: a novel class of anticancer agents targeting cell signaling pathways and other bioactivities. Future Med Chem 5:809–829.  https://doi.org/10.4155/fmc.13.32 CrossRefGoogle Scholar
  17. 17.
    Arora S, Singh S, Piazza GA, Contreras CM, Panyam J, Singh AP (2012) Honokiol: a novel natural agent for cancer prevention and therapy. Curr Mol Med 12:1244–1252.  https://doi.org/10.2174/156652412803833508 CrossRefGoogle Scholar
  18. 18.
    Lee YJ, Lee YM, Lee CK, Jung JK, Han SB, Hong JT (2011) Therapeutic applications of compounds in the Magnolia family. Pharmacol Ther 130:157–176.  https://doi.org/10.1016/j.pharmthera.2011.01.010 CrossRefGoogle Scholar
  19. 19.
    Wang L, Waltenberger B, Pferschy-Wenzig EM, Blunder M, Liu X, Malainer C, Blazevic T, Schwaiger S, Rollinger JM, Heiss EH, Schuster D, Kopp B, Bauer R, Stuppner H, Dirsch VM, Atanasov AG (2014) Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARgamma): a review. Biochem Pharmacol 92:73–89.  https://doi.org/10.1016/j.bcp.2014.07.018 CrossRefGoogle Scholar
  20. 20.
    Munroe ME, Arbiser JL, Bishop GA (2007) Honokiol, a natural plant product, inhibits inflammatory signals and alleviates inflammatory arthritis. J Immunol 179:753–763.CrossRefGoogle Scholar
  21. 21.
    Chilampalli C, Zhang X, Kaushik RS, Young A, Zeman D, Hildreth MB, Fahmy H, Dwivedi C (2013) Chemopreventive effects of combination of honokiol and magnolol with alpha-santalol on skin cancer developments. Drug Discov Ther 7:109–115.  https://doi.org/10.5582/ddt.2013.v7.3.109 Google Scholar
  22. 22.
    Shigemura K, Arbiser JL, Sun SY, Zayzafoon M, Johnstone PA, Fujisawa M, Gotoh A, Weksler B, Zhau HE, Chung LW (2007) Honokiol, a natural plant product, inhibits the bone metastatic growth of human prostate cancer cells. Cancer 109:1279–1289.CrossRefGoogle Scholar
  23. 23.
    Ishitsuka K, Hideshima T, Hamasaki M, Raje N, Kumar S, Hideshima H, Shiraishi N, Yasui H, Roccaro AM, Richardson P, Podar K, Le Gouill S, Chauhan D, Tamura K, Arbiser J, Anderson KC (2005) Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis. Blood 106:1794–1800CrossRefGoogle Scholar
  24. 24.
    Dai X, Cheng H, Bai Z, Li J (2017) Breast Cancer Cell Line Classification and Its Relevance with Breast Tumor Subtyping. J Cancer 8:3131–3141.  https://doi.org/10.7150/jca.18457 CrossRefGoogle Scholar
  25. 25.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408.  https://doi.org/10.1006/meth.2001.1262 CrossRefGoogle Scholar
  26. 26.
    Pishvaian MJ, Feltes CM, Thompson P, Bussemakers MJ, Schalken JA, Byers SW (1999) Cadherin-11 is expressed in invasive breast cancer cell lines. Cancer Res 59:947–952.  https://doi.org/10.3892/ol.2016.5236 Google Scholar
  27. 27.
    Haxho F, Neufeld RJ, Szewczuk MR (2016) Neuraminidase-1: a novel therapeutic target in multistage tumorigenesis. Oncotarget 7:40860–40881.  https://doi.org/10.18632/oncotarget.8396 CrossRefGoogle Scholar
  28. 28.
    Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y, Johnson KR (2008) Cadherin switching. J Cell Sci 121:727–735.  https://doi.org/10.1242/jcs.000455 CrossRefGoogle Scholar
  29. 29.
    Tamura D, Hiraga T, Myoui A, Yoshikawa H, Yoneda T (2008) Cadherin-11-mediated interactions with bone marrow stromal/osteoblastic cells support selective colonization of breast cancer cells in bone. Int J Oncol 33:17–24.Google Scholar
  30. 30.
    Hama R, Bennett CL (2017) The mechanisms of sudden-onset type adverse reactions to oseltamivir. Acta Neurol Scand 135:148–160.  https://doi.org/10.1111/ane.12629 CrossRefGoogle Scholar
  31. 31.
    Chio CC, Tai YT, Mohanraj M, Liu SH, Yang ST, Chen RM (2018) Honokiol enhances temozolomide-induced apoptotic insults to malignant glioma cells via an intrinsic mitochondrion-dependent pathway. Phytomedicine 49:41–51.  https://doi.org/10.1016/j.phymed.2018.06.012 CrossRefGoogle Scholar
  32. 32.
    Ji N, Jiang L, Deng P, Xu H, Chen F, Liu J, Li J, Liao G, Zeng X, Lin Y, Feng M, Li L, Chen Q (2017) Synergistic effect of honokiol and 5-fluorouracil on apoptosis of oral squamous cell carcinoma cells. J Oral Pathol Med 46:201–207.  https://doi.org/10.1111/jop.12481 CrossRefGoogle Scholar
  33. 33.
    Thulasiraman P, Johnson AB (2016) Regulation of Mucin 1 and multidrug resistance protein 1 by honokiol enhances the efficacy of doxorubicin-mediated growth suppression in mammary carcinoma cells. Int J Oncol 49:479–486.  https://doi.org/10.3892/ijo.2016.3534 CrossRefGoogle Scholar
  34. 34.
    Zhang Z, Wuhrer M, Holst S (2018) Serum sialylation changes in cancer. Glycoconj J 35:139–160.  https://doi.org/10.1007/s10719-018-9820-0 CrossRefGoogle Scholar
  35. 35.
    Gavrilov Y, Shental-Bechor D, Greenblatt HM, Levy Y (2015) Glycosylation may reduce protein thermodynamic stability by inducing a conformational distortion. J Phys Chem Lett 6:3572–3577.  https://doi.org/10.1021/acs.jpclett.5b01588 CrossRefGoogle Scholar
  36. 36.
    Vajaria BN, Patel KR, Begum R, Patel PS (2016) Sialylation: an avenue to target cancer cells. Pathol Oncol Res 22:443–447.  https://doi.org/10.1007/s12253-015-0033-6 CrossRefGoogle Scholar
  37. 37.
    Bull C, Stoel MA, den Brok MH, Adema GJ (2014) Sialic acids sweeten a tumor’s life. Cancer Res 74:3199–3204.  https://doi.org/10.1158/0008-5472.CAN-14-0728 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Biomedical SciencesCollege of Allied Health, University of South AlabamaMobileUSA

Personalised recommendations