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dc.contributor.authorAnoopkumar-Dukie, Shailendra
dc.contributor.authorConere, Tom
dc.contributor.authorHouston, Aileen
dc.contributor.authorKing, Liam
dc.contributor.authorChristie, David
dc.contributor.authorMcDermott, Catherine
dc.contributor.authorAllshire, Ashley
dc.date.accessioned2020-10-14T01:33:47Z
dc.date.available2020-10-14T01:33:47Z
dc.date.issued2020
dc.identifier.issn1098-8823
dc.identifier.doi10.1016/j.prostaglandins.2020.106422
dc.identifier.urihttp://hdl.handle.net/10072/398355
dc.description.abstractIt is widely accepted that the hypoxic nature of solid tumors contribute to their resistance to radiation therapy. There is increasing evidence that cyclooxygenase-2 (COX-2) contributes to increased resistance of tumors to radiation therapy. Several studies demonstrate that combination of COX-2 selective inhibitors with radiation therapy selectively enhances radio responsiveness of tumor cells. However, the majority of these studies utilised suprapharmacological concentrations under normoxic conditions only. Furthermore, the mechanism by which these agents act remain largely unclear. Therefore, the aim of this study was to determine the impact of COX-2 selective inhibitors on both normoxic and hypoxic radiosensitivity in vitro and the mechanisms underlying this. Because of the close, reciprocal relationship between COX-2 and p53 we investigated their contribution to radioresistance. To achieve this we exposed HeLa, MCF-7 and MeWo cells to the COX-2 selective inhibitor, NS398 (10μM). NS398 (10μM) selectively sensitized hypoxic HeLa and MCF-7 but not MeWo cells to ionising radiation (5 Gy). Furthermore, while knockdown of COX-2 with siRNA did not affect either normoxic radiosensitivity in HeLa cells, the radiosensitisation observed with NS398 was lost suggesting both COX-2 dependent and independent mechanisms. We also show that ionising radiation at 5 Gy results in phosphorylation of p53 at serine 15, a key phosphorylation site for p53-mediated apoptosis, and that hypoxia attenuates this phosphorylation. Attenuated phosphorylation of p53 under hypoxic conditions may therefore contribute to hypoxic radioresistance. We also show that NS398 selectively phosphorylates p53 under hypoxic conditions following irradiation at 5 Gy. p53 phosphorylation could be an underlying mechanism by which this agent and other COX-2 inhibitors sensitize tumors to radiation therapy.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherElsevier
dc.relation.ispartofpagefrom106422
dc.relation.ispartofjournalProstaglandins & Other Lipid Mediators
dc.relation.ispartofvolume148
dc.subject.fieldofresearchMedical biochemistry and metabolomics
dc.subject.fieldofresearchcode3205
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsBiochemistry & Molecular Biology
dc.subject.keywordsCell Biology
dc.subject.keywordsCOX-2
dc.titleThe COX-2 inhibitor NS398 selectively sensitizes hypoxic HeLa cells to ionising radiation by mechanisms both dependent and independent of COX-2
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationAnoopkumar-Dukie, S; Conere, T; Houston, A; King, L; Christie, D; McDermott, C; Allshire, A, The COX-2 inhibitor NS398 selectively sensitizes hypoxic HeLa cells to ionising radiation by mechanisms both dependent and independent of COX-2, Prostaglandins & Other Lipid Mediators, 2020, 148
dcterms.dateAccepted2020-01-24
dc.date.updated2020-10-14T01:29:24Z
gro.hasfulltextNo Full Text
gro.griffith.authorAnoopkumar-Dukie, Shailendra


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