Journal
CELLULAR SIGNALLING
Volume 25, Issue 12, Pages 2587-2603Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2013.08.008
Keywords
Neuraminidase-1; Matrix metalloproteinase-9; Pancreatic cancer
Categories
Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Franklin Bracken Scholarship
- R.S. McLaughlin Scholarship
- Ontario Graduate Scholarship
- Canadian Institutes of Health Research (CIHR)
- Ministry of Higher Education, Saudi Arabia
- Queen's Graduate Award
- Robert J. Wilson Fellowship
- NSERC USRA
- Mitacs Globalink program
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Epidermal growth factor (EGF)-induced EGFR tyrosine kinase receptor activation in cancer cell survival responses has become a strategic molecular-targeting clinical therapeutic intent, but the failures of these targeted approaches in the clinical setting demand alternate strategies. Here, we uncover a novel neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with GPCR neuromedin B, which is essential for EGF-induced receptor activation and cellular signaling. Neu1 and MMP-9 form a complex with EGFR on the cell surface. Tamiflu (oseltamivir phosphate), anti-Neu1 antibodies, broad range MMP inhibitor galardin (GM6001), neuromedin B GPCR specific antagonist BIM-23127, the selective inhibitor of whole heterotrimeric G-protein complex BIM-46174 and MMP-9 specific inhibitor dose-dependently inhibited Neu1 activity associated with EGF stimulated 3T3-hEGFR cells. Tamiflu, anti-Neu1 antibodies and MMP9i attenuated EGFR phosphorylation associated with EGF-stimulated cells. Preclinical data provide the proof-of-evidence for a therapeutic targeting of Neu1 with Tamiflu in impeding human pancreatic cancer growth and metastatic spread in heterotopic xenografts of eGFP-MiaPaCa-2 tumors growing in RAGxC gamma double mutant mice. Tamiflu-treated cohort exhibited a reduction of phosphorylation of EGFR-Tyr1173, Stat1-Tyr701, Akt-Thr308, PDGFR alpha-Tyr754 and NF kappa Bp65-Ser311 but an increase in phospho-Smad2-Ser465/467 and -VEGFR2-Tyr1175 in the tumor lysates from the xenografts of human eGFP-MiaPaCa-2 tumor-bearing mice. The findings identify a novel promising alternate therapeutic treatment of human pancreatic cancer. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.
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