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Review
. 2016 Jun 28;7(26):40860-40881.
doi: 10.18632/oncotarget.8396.

Neuraminidase-1: a novel therapeutic target in multistage tumorigenesis

Fiona Haxho  1 , Ronald J Neufeld  2 , Myron R Szewczuk  1
Affiliations
Review

Neuraminidase-1: a novel therapeutic target in multistage tumorigenesis

Fiona Haxho et al. Oncotarget. .

Abstract

Several of the growth factors and their receptor tyrosine kinases (RTK) such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and insulin are promising candidate targets for cancer therapy. Indeed, tyrosine kinase inhibitors (TKI) have been developed to target these growth factors and their receptors, and have demonstrated dramatic initial responses in cancer therapy. Yet, most patients ultimately develop TKI drug resistance and relapse. It is essential in the clinical setting that the targeted therapies are to circumvent multistage tumorigenesis, including genetic mutations at the different growth factor receptors, tumor neovascularization, chemoresistance of tumors, immune-mediated tumorigenesis and the development of tissue invasion and metastasis. Here, we identify a novel receptor signaling platform linked to EGF, NGF, insulin and TOLL-like receptor (TLR) activations, all of which are known to play major roles in tumorigenesis. The importance of these findings signify an innovative and promising entirely new targeted therapy for cancer. The role of mammalian neuraminidase-1 (Neu1) in complex with matrix metalloproteinase-9 and G protein-coupled receptor tethered to RTKs and TLRs is identified as a major target in multistage tumorigenesis. Evidence exposing the link connecting growth factor-binding and immune-mediated tumorigenesis to this novel receptor-signaling paradigm will be reviewed in its current relationship to cancer.

Keywords: Neu1; cancer; metastasis; oseltamivir phosphate; tumor angiogenesis.

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Conflict of interest statement

CONFLICTS OF INTERESTS The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP9) cross-talk in alliance with G protein-coupled receptor(s) (GPCR) regulates receptor tyrosine kinases (RTKs)
Notes: Snail and MMP9 expressions are closely connected in invasive tumor processes. Snail induces MMP9 secretion via multiple signaling pathways, but particularly in cooperation with oncogenic H-Ras (RasV12), Snail up-regulates the transcription of MMP9. This Snail-MMP9 signaling axis is the connecting link to promote RTK glycosylation modification involving this novel receptor-signaling platform. Activated MMP9 is proposed to remove the elastin-binding protein (EBP) as part of the molecular multi-enzymatic complex that contains β-galactosidase/Neu1 and protective protein cathepsin A (PPCA) to induce Neu1. Activated Neu1 hydrolyzes α-2,3-sialic acid residues of the glycosylated receptors at the ectodomain to remove steric hindrance and to facilitate receptor association and activation. This process sets the stage for multistages of tumorigenesis. Abbreviations: Neu1, neuraminidase-1; MMP, matrix metalloproteinase; PI3K, phosphatidylinositol 3-kinase; GTP, guanine triphosphate; GPCR, G protein-coupled receptor; EBP, elastin binding protein; PPCA, protective protein cathepsin A. Citation: Taken in part from: ©Abdulkhalek et al. Research and Reports in Biochemistry 2013:3,17–30, and ©Abdulkhalek et al. Clinical and Translational Medicine 2014:3,28. Publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted non-commercial use, provided the original work is properly cited.
Figure 2
Figure 2. Neu1-MMP9-GPCR signaling platform in the regulation of RTK and the molecular targeting of multistage tumorigenesis
Neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP9) cross-talk in alliance with G protein-coupled receptor(s) (GPCR) regulates receptor tyrosine kinases (RTKs) and extracellular and intracellular TOLL-like (TLR) receptors in cancer cells. This process sets the stage for multistage tumorigenesis. Abbreviations: Neu1, neuraminidase-1; MMP, matrix metalloproteinase; IRβ, insulin receptor β; EGCR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transition; 5-FU, 5-fluorouracil; PI3K, phosphatidylinositol 3-kinase; GTP, guanine triphosphate; GPCR, G protein-coupled receptor; EBP, elastin binding protein; PPCA, protective protein cathepsin A. Citation: Taken in part from: ©Abdulkhalek et al. Research and Reports in Biochemistry 2013:3,17–30, and ©Abdulkhalek et al. Clinical and Translational Medicine 2014:3,28. Publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted non-commercial use, provided the original work is properly cited.
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