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dc.contributor.authorHaxho, Fionaen
dc.date.accessioned2017-08-10T15:15:23Z
dc.date.available2017-08-10T15:15:23Z
dc.identifier.urihttp://hdl.handle.net/1974/22001
dc.description.abstractThe abnormal expression of cell surface sialic acid has recently been identified as an important trait of cancer cells. The main sialylation-modifying enzyme in mammalian cells, neuraminidase-1 (Neu1), has been shown to positively regulate several receptors and their activation, including the epidermal growth factor receptor (EGFR), insulin receptor (IR), and a number of TOLL-like receptors (TLR). Notably, these receptors each play unique and profound roles in tumor development and progression via promotion of cell proliferation and survival pathways, cell growth and metabolism, and immune-mediated tumorigenesis, respectively. Here, we further characterize the role of Neu1 in cancer cell signaling, as well as tumor growth, neovascularization and metastasis. Furthermore, the molecular targeting of Neu1 using competitive inhibitor and sialic acid analog oseltamivir phosphate (OP) has been evaluated for its therapeutic role in suppressing tumor progression. This report uncovers the molecular mechanisms that regulate the role of Neu1 sialidase in insulin receptor activation. Specifically, we show that GPCR agonists bombesin, bradykinin, angiotensin I and angiotensin II can stimulate Neu1 sialidase activity to induce IR activation (phosphorylation) in the absence of insulin. Furthermore, this effect can be blocked by GPCR inhibitor BIM-23127 as well as OP. The studies in this report also investigated the effect of OP in murine models of human triple-negative breast cancer (MDA-MB-231), ovarian endometrial cancer (A2780), and pancreatic ductal adenocarcinoma (PANC1) tumor xenografts growing in RAGxCγ mice. In comparison to untreated groups, OP treatment resulted in a significant reduction in tumor volume, metastatic spread to the mouse liver and lungs, as well as a reduction in tumor-associated neovascularization and recruitment of host endothelial cells. In conclusion, these findings provide insight into the novel targeting of tumor-promoting pathways via Neu1 sialidase and implicate OP as a novel agent in cancer therapy.en
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectNeuraminidaseen
dc.subjectGrowth Factor Receptoren
dc.subjectCellular Signalingen
dc.subjectGlycobiologyen
dc.subjectReceptor Glycosylationen
dc.subjectSialic Aciden
dc.subjectHuman Canceren
dc.titleRole of Neuraminidase-1 in Cancer Development and Clinical Implicationsen
dc.typethesisen
dc.description.degreePhDen
dc.contributor.supervisorSzewczuk, Myronen
dc.contributor.departmentBiomedical and Molecular Sciencesen
dc.embargo.termsUnpublished dataen
dc.embargo.liftdate2022-08-10T13:25:21Z
dc.degree.grantorQueen's University at Kingstonen


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