title: A novel epidermal growth factor receptor-signaling platform and its targeted translation in pancreatic cancer.
abstract: 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.
authors.affiliation: Department of Biomedical & Molecular Sciences, Queen's University, Kingston, ON K7L3N6, Canada. Electronic address: alanna.m.gilmour@gmail.com.
authors.forename: Alanna M
authors.initials: AM
authors.lastname: Gilmour
authors.forename: Samar
authors.initials: S
authors.lastname: Abdulkhalek
authors.forename: Timothy S W
authors.initials: TS
authors.lastname: Cheng
authors.forename: Farah
authors.initials: F
authors.lastname: Alghamdi
authors.forename: Preethi
authors.initials: P
authors.lastname: Jayanth
authors.forename: Leah K
authors.initials: LK
authors.lastname: O'Shea
authors.forename: Olivia
authors.initials: O
authors.lastname: Geen
authors.forename: Luis A
authors.initials: LA
authors.lastname: Arvizu
authors.forename: Myron R
authors.initials: MR
authors.lastname: Szewczuk
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009439:Neuraminidase / Q000378:metabolism; D053139:Oseltamivir / Q000627:therapeutic use*; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D053139:Oseltamivir; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D009439:Neuraminidase; D020780:Matrix Metalloproteinase 9
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