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 RAGxCγ double mutant mice. Tamiflu-treated cohort exhibited a reduction of phosphorylation of EGFR-Tyr1173, Stat1-Tyr701, Akt-Thr308, PDGFRα-Tyr754 and NFκBp65-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.
Keywords: 0EGF; 4-MUNANA; Akt; Cγ; FGF; IC(50); MMP; Matrix metalloproteinase-9; NGF; Neu1; Neuraminidase-1; PDGF; Pancreatic cancer; RAG2; RTKs; SMAD2; STAT1; TLR; TOLL-like receptor; VEGF; [2′-(4-methylyumbelliferyl)-α-D-N-acetylneuraminic acid]; combining recombinase activating gene-2; common cytokine receptor γ chain; epidermal growth factor; fibroblast growth factor; mammalian neuraminidase-1; matrix metalloproteinase; mothers against decapentaplegic homolog-2 signal transducer and transcriptional modulator; nerve growth factor; platelet-derived growth factor; protein kinase B (PKB) a serine/threonine-specific protein kinase; receptor tyrosine kinases; signal transducer and activator of transcription-1, 91kDa; the concentration of a drug that is required for 50% inhibition in vitro; vascular endothelial growth factor.
© 2013. Published by Elsevier Inc. All rights reserved.