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      Novel Molecular Mechanism of Aspirin and Celecoxib Targeting Mammalian Neuraminidase-1 Impedes Epidermal Growth Factor Receptor Signaling Axis and Induces Apoptosis in Pancreatic Cancer Cells

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          Aspirin (acetylsalicylic acid) and celecoxib have been used as potential anti-cancer therapies. Aspirin exerts its therapeutic effect in both cyclooxygenase (COX)-dependent and -independent pathways to reduce tumor growth and disable tumorigenesis. Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, reduces factors that cause inflammation and pain. The question is whether aspirin and celecoxib have other molecular targets of equal or more therapeutic efficacy with significant anti-cancer preventive benefits.


          Here, we propose that aspirin and celecoxib exert their anti-cancer effects by targeting and inhibiting mammalian neuraminidase-1 (Neu-1). Neu-1 has been reported to regulate the activation of several receptor tyrosine kinases (RTKs) and TOLL-like receptors and their downstream signaling pathways. Neu-1 in complex with matrix metalloproteinase-9 (MMP-9) and G protein-coupled receptors (GPCRs) has been reported to be tethered to RTKs at the ectodomain.

          Materials and Methods

          The WST-1 cell viability assay, Caspase 3/7 assay, and Annexin V assay were used to evaluate the cell viability and detect apoptotic and necrotic cells following treatment in MiaPaCa-2, PANC-1 and the gemcitabine-resistant PANC-1 variant (PANC-1 GemR) cells. Microscopic imaging, lectin cytochemistry, and flow cytometry were used to detect levels of α-2,3 sialic acid. Epidermal growth factor (EGF)-stimulated live cell sialidase assays and neuraminidase assays were used to detect Neu-1 activity. Immunocytochemistry was used to detect levels of EGFR and phosphorylated EGFR (pEGFR) following treatment.


          For the first time, aspirin and celecoxib were shown to significantly inhibit Neu-1 sialidase activity in a dose- and time-dependent manner following stimulation with EGF. Aspirin blocked Neu-1 desialylation of α-2,3-sialic acid expression following 30 min stimulation with EGF. Aspirin and celecoxib significantly and dose-dependently inhibited isolated neuraminidase ( Clostridium perfringens) activity on fluorogenic substrate 2ʹ-(4-methylumbelliferyl)-α-D-N-acetylneuraminic acid (4-MUNANA). Aspirin inhibited phosphorylation of the EGFR in EGF-stimulated cells. Aspirin dose- and time-dependently induced CellEvent caspase-3/7 + cells as well as apoptosis and necrosis on PANC-1 cells.


          These findings signify a novel multimodality mechanism(s) of action for aspirin and celecoxib, specifically targeting and inhibiting Neu-1 activity, regulating EGF-induced growth receptor activation and inducing apoptosis and necrosis in a dose- and time-dependent manner. Repurposing aspirin and celecoxib as anti-cancer agents may also upend other critical targets involved in multistage tumorigenesis regulated by mammalian neuraminidase-1.


          These findings may be the missing link connecting the anti-cancer efficacy of NSAIDs to the role of glycosylation in inflammation and tumorigenesis.

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          Most cited references 62

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                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                08 October 2020
                : 14
                : 4149-4167
                [1 ]Department of Biomedical and Molecular Sciences, Queen’s University , Kingston, ON K7L 3N6, Canada
                [2 ]ENCYT Technologies Inc ., Membertou, Nova Scotia, Canada
                Author notes
                Correspondence: Myron R Szewczuk Department of Biomedical and Molecular Sciences, Queen’s University , Kingston, ONK7L 3N6, CanadaTel +1 613 533 2457Fax +1 613 533 6796; Email szewczuk@queensu.ca
                © 2020 Qorri et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 8, References: 63, Pages: 19
                Funded by: the Natural Sciences and Engineering Research Council of Canada (NSERC);
                Funded by: the Josefowitz Family to MRS, and Encyt Technologies Inc;
                This study was supported by grants to MRS from the Natural Sciences and Engineering Research Council of Canada (NSERC), private-sector cancer funding from the Josefowitz Family to MRS, and Encyt Technologies Inc. BQ is the recipient of 2017, 2018, and 2019 Queen’s Graduate Award (QGA), Terry Fox Research Institute Transdisciplinary Training Program in Cancer Research (2017), the 2018 and 2019 Dean’s Doctoral Award, the 2019 Franklin Bracken Fellowship, and the 2020 Queen Elizabeth II Graduate Scholarship in Science and Technology.
                Original Research


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