期刊
DRUG DESIGN DEVELOPMENT AND THERAPY
卷 14, 期 -, 页码 4149-4167出版社
DOVE MEDICAL PRESS LTD
DOI: 10.2147/DDDT.S264122
关键词
neuraminidase-1; inflammation; cancer; multistage tumorigenesis; tumor microenvironment
资金
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Josefowitz Family
- Encyt Technologies Inc.
- 2017 Queen's Graduate Award (QGA)
- 2018 Queen's Graduate Award (QGA)
- 2019 Queen's Graduate Award (QGA)
- Terry Fox Research Institute Transdisciplinary Training Program in Cancer Research (2017)
- 2018 Dean's Doctoral Award
- 2019 Dean's Doctoral Award
- 2019 Franklin Bracken Fellowship
- 2020 Queen Elizabeth II Graduate Scholarship in Science and Technology
Background: Aspirin (acetylsalicylic acid) and celecoxib have been used as potential anticancer 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. Aim: 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 alpha-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. Results: 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 alpha-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 2'-(4-methylumbelliferyl)-alpha-D-N-acetylneuraminic acid (4-MUNANA). Aspirin inhibited phosphorylation of the EGFR in EGF-stimulated cells. Aspirin dose- and time-dependently induced Cell-Event caspase-3/7(+) cells as well as apoptosis and necrosis on PANC-1 cells. Conclusion: 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. Significance: 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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