Abstract
Purpose
Newcastle disease virus (NDV) has been applied to oncolytic virotherapy for decades due to its naturally oncolytic property. In spite of the substantiation of the sialic acid receptors of NDV on host cells, knowledge of preference of sialic acid linkage in viral attachment and oncolytic effect is lacking and imperative to be elucidated.
Methods
Surface plasmon resonance analysis and competitive inhibition with sialylated glycan receptor analogues were used to determine the affinity and the preference of sialic acid receptor. Treatments of sialyltransferase inhibitors and linkage-specific sialidases and transfection with sialyltransferase expression vector were performed to regulate sialic acids levels.
Results
We demonstrated that sialic acid was essential for NDV binding and infection of tumor cells. α2,6-linked sialic acid served as a high-affinity receptor for NDV and the ST6Gal I sialyltransferase that synthesizes α2-6 linkage of sialylated N-linked glycans in CHO-K1 cells promoted NDV binding and cytopathic effect. More importantly, an enhanced antitumor effect of NDV on aggressive SW620 colorectal carcinoma cells with high-level of cell surface α2,6-sialylation, but not SW480 cells with relative low-level of α2,6-sialylation, was observed both in vitro and in vivo.
Conclusions
The study provides evidence of optimized therapeutic strategy in oncolytic virotherapy via partly defining α2,6-sialylated receptor as a “cellular marker” for NDV.
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Abbreviations
- F:
-
Fusion
- FBS:
-
Fetal bovine serum
- FITC:
-
Fluorescein isothiocyanate
- Gal:
-
Galactose
- GalNAc:
-
N-acetylgalactosamine
- HN:
-
Hemagglutinin-neuraminidase
- K a :
-
Association constant
- K d :
-
Dissociation constant
- K D :
-
Equilibrium dissociation constant
- MAA:
-
Maackia amurensis lectin
- MAL II:
-
Maackia amurensis lectin II
- MOI:
-
Multiplicity of infection
- NDV:
-
Newcastle disease virus
- Neu5Ac:
-
N-acetylneuraminic acid
- Pfu:
-
Plaque forming unit
- RPMI-1640:
-
Roswell Park Memorial Institute-1640 medium
- Sia:
-
Sialic acids
- ST6GAL1:
-
2,6-sialyltransferase
- 3′SLN:
-
3′-sialyl-N-acetyllactosamine
- 6′SLN:
-
6′-sialyl-N-acetyllactosamine
- SNA:
-
Sambucus nigra
- STs:
-
Sialyltransferases
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Acknowledgments
The authors thank Prof. Volker Schirrmacher (German Cancer Research Center, Germany) for the gift of NDV Italien.
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Funding
This work was supported by grants from the National Natural Science Foundation of China (31571434, 81172144, 81201776) and the National Science and Technology Major Project (2015CB553701, 2012ZX10002-015, 2012AA020806).
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All authors have read the journal’s policy on disclosure of potential conflicts of interest and have none to declare. All authors have read the journal’s authorship agreement, and the manuscript has been reviewed and approved by all named authors.
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Li, Q., Wei, D., Feng, F. et al. α2,6-linked sialic acid serves as a high-affinity receptor for cancer oncolytic virotherapy with Newcastle disease virus. J Cancer Res Clin Oncol 143, 2171–2181 (2017). https://doi.org/10.1007/s00432-017-2470-y
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DOI: https://doi.org/10.1007/s00432-017-2470-y