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Sialidase Attenuates Epidermal Growth Factor Response and Abolishes Antiproliferative Effects of Erlotinib in A549Alveolar Epithelial Cells

  • A. RybakEmail author
  • M. Zarzecki
  • E. Golabiewska
  • A. Niechoda
  • A. Holownia
Chapter
Part of the Advances in Experimental Medicine and Biology book series

Abstract

Erlotinib is a widely used, reversible tyrosine kinase inhibitor (TKI), targeting pro-proliferative signaling of epidermal growth factor receptor (EGFR). The drug is approved for the first-line treatment of patients with metastatic non-small cell lung cancer with EGFR mutations. Extracellular glycans can affect EGFR expression, dimerization, phosphorylation, and EGF binding. In this study we investigated the effects of EGF and erlotinib on the cell cycle of naive and sialidase (alpha-neuraminidase)-pretreated human A549 alveolar epithelial cells. A549 cells were labeled with propidium iodide, and fractions of cells in different phases of cycle were quantified by flow cytometry. We found that neither did desialilation nor EGF, as well as erlotinib treatment, increase the number of damaged cells (subG0/G1 cell fraction), while erlotinib did significantly increase the number of G0/G1 cells and decrease S + G2/M cell fractions. In naive cells, EGF increased proliferating cell numbers by more than 40%, and this effect was blocked by erlotinib. In desialylated cells, however, proliferation was significantly decreased by about 29%, and EGF and erlotinib did not exert significant effects. We conclude that changes in alveolar epithelial cell membrane glycosylation may affect function of growth-promoting receptors and erlotinib effectiveness.

Keywords

A549 cells Alveolar epithelial cells Cell cycle Epidermal growth factor Erlotinib Sialidase 

Notes

Conflicts of Interest

The authors had no conflicts of interest to declare in relation to this article.

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. Britain CM, Holdbrooks AT, Anderson JC, Willey CD, Bellis SL (2018) Sialylation of EGFR by the ST6Gal–I sialyltransferase promotes EGFR activation and resistance to gefitinib–mediated cell death. J Ovarian Res 11:12Google Scholar
  2. Forcella M, Oldani M, Epistolio S, Freguia S, Monti E, Fusi P, Frattini M (2017) Non–small cell lung cancer (NSCLC), EGFR downstream pathway activation and TKI targeted therapies sensitivity: effect of the plasma membrane–associated NEU3. PLoS One 12:e0187289Google Scholar
  3. Gridelli C, Bareschino MA, Schettino C, Rossi A, Maione P, Ciardiello F (2007) Erlotinib in non–small cell lung cancer treatment: current status and future development. Oncologist 12:840–849Google Scholar
  4. Lillehoj EP, Hyun SW, Feng C, Zhang L, Liu A, Guang W, Nguyen C, Luzina IG, Atamas SP, Passaniti A, Twaddell WS, Puché AC, Wang LX, Cross AS, Goldblum SE (2012) NEU1 sialidase expressed in human airway epithelia regulates epidermal growth factor receptor (EGFR) and MUC1 protein signaling. J Biol Chem 287:8214–8231Google Scholar
  5. Lindsey S, Langhans SA (2015) Epidermal growth factor signaling in transformed cells. Int Rev Cell Mol Biol 314:1–41Google Scholar
  6. Liu YC, Yen HY, Chen CY, Chen CH, Cheng PF, Juan YH, Chen CH, Khoo KH, Yu CJ, Yang PC, Hsu TL, Wong CH (2011) Sialylation and fucosylation of epidermal growth factor receptor suppress its dimerization and activation in lung cancer cells. Proc Natl Acad Sci U S A 108:11332–11337Google Scholar
  7. Manhardt CT, Punch PR, Dougher CWL, Lau JTY (2017) Extrinsic sialylation is dynamically regulated by systemic triggers in vivo. J Biol Chem 292:13514–13520Google Scholar
  8. Mitsudomi T, Yatabe Y (2010) Epidermal growth factor receptor in relation to tumour development: EGFR gene and cancer. FEBS J 277:301–308Google Scholar
  9. Miyagi T, Yamaguchi K (2012) Mammalian sialidases: physiological and pathological roles in cellular functions. Glycobiology 22:880–896Google Scholar
  10. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA (2008) Non–small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 83:584–594Google Scholar
  11. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W, National Cancer Institute of Canada Clinical Trials Group (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966Google Scholar
  12. Orcutt KP, Parsons AD, Sibenaller ZA, Scarbrough PM, Zhu Y, Sobhakumari A, Wilke WW, Kalen AL, Goswami P, Miller FJ Jr, Spitz DR, Simons AL (2011) Erlotinib–mediated inhibition of EGFR signaling induces metabolic oxidative stress through NOX4. Cancer Res 71:3932–3940Google Scholar
  13. Park JJ, Yi JY, Jin YB, Lee YJ, Lee JS, Lee YS, Ko YG, Lee M (2012) Sialylation of epidermal growth factor receptor regulates receptor activity and chemosensitivity to gefitinib in colon cancer cells. Biochem Pharmacol 83:849–857Google Scholar
  14. Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225Google Scholar
  15. Shan F, Shao Z, Jiang S, Cheng Z (2016) Erlotinib induces the human non–small–cell lung cancer cells apoptosis via activating ROS–dependent JNK pathways. Cancer Med 5:3166–3175Google Scholar
  16. Sharma SV, Settleman J (2009) ErbBs in lung cancer. Exp Cell Res 315:557–571Google Scholar
  17. Sharma SV, Bell DW, Settleman J, Haber DA (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7:169–181Google Scholar
  18. Takahashi M, Hasegawa Y, Gao C, Kuroki Y, Taniguchi N (2016) N–glycans of growth factor receptors: their role in receptor function and disease implications. Clin Sci (Lond) 130:1781–1792Google Scholar
  19. Vajaria BN, Patel KR, Begum R, Patel PS (2016) Sialylation: an avenue to target cancer cells. Pathol Oncol Res 22:443–447Google Scholar
  20. Wada T, Hata K, Yamaguchi K, Shiozaki K, Koseki K, Moriya S, Miyagi T (2007) A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells. Oncogene 26:2483–2490Google Scholar
  21. Wu WS, Chen YM, Tsai CM, Shih JF, Chiu CH, Chou KT, Lai SL, Wu CH, Luo YH, Huang CY, Lee YC, Perng RP, Whang-Peng J (2012) Erlotinib has better efficacy than gefitinib in adenocarcinoma patients without EGFR-activating mutations, but similar efficacy in patients with EGFR-activating mutations. Exp Ther Med 3:207–213Google Scholar
  22. Yen HY, Liu YC, Chen NY, Tsai CF, Wang YT, Chen YJ, Hsu TL, Yang PC, Wong CH (2015) Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition. Proc Natl Acad Sci U S A 112:6955–6960Google Scholar
  23. Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ (2008) The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A 105:2070–2075Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • A. Rybak
    • 1
    Email author
  • M. Zarzecki
    • 1
  • E. Golabiewska
    • 1
  • A. Niechoda
    • 1
  • A. Holownia
    • 1
  1. 1.Department of PharmacologyMedical University of BialystokBialystokPoland

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