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dc.contributor.authorAl-Saraireh, Yousef M.J.*
dc.contributor.authorSutherland, Mark H.*
dc.contributor.authorSpringett, Bradley R.*
dc.contributor.authorFreiberger, F.*
dc.contributor.authorRibeiro Morais, Goreti*
dc.contributor.authorLoadman, Paul M.*
dc.contributor.authorErrington, R.J.*
dc.contributor.authorSmith, P.J.*
dc.contributor.authorFukuda, M.*
dc.contributor.authorGerardy-Schahn, R.*
dc.contributor.authorPatterson, Laurence H.*
dc.contributor.authorShnyder, Steven D.*
dc.contributor.authorFalconer, Robert A.*
dc.date.accessioned2016-08-12T15:24:20Z
dc.date.available2016-08-12T15:24:20Z
dc.date.issued2013-08-09
dc.identifier.citationAl-Saraireh YMJ, Sutherland MH, Springett BR et al (2013) Pharmacological Inhibition of polysialyltransferase ST8SiaII Modulates Tumour Cell Migration. PLoS ONE 8(8): e73366.en_US
dc.identifier.urihttp://hdl.handle.net/10454/8780
dc.descriptionYesen_US
dc.description.abstractPolysialic acid (polySia), an α-2,8-glycosidically linked polymer of sialic acid, is a developmentally regulated posttranslational modification predominantly found on NCAM (neuronal cell adhesion molecule). Whilst high levels are expressed during development, peripheral adult organs do not express polySia-NCAM. However, tumours of neural crest-origin re-express polySia-NCAM: its occurrence correlates with aggressive and invasive disease and poor clinical prognosis in different cancer types, notably including small cell lung cancer (SCLC), pancreatic cancer and neuroblastoma. In neuronal development, polySia-NCAM biosynthesis is catalysed by two polysialyltransferases, ST8SiaII and ST8SiaIV, but it is ST8SiaII that is the prominent enzyme in tumours. The aim of this study was to determine the effect of ST8SiaII inhibition by a small molecule on tumour cell migration, utilising cytidine monophosphate (CMP) as a tool compound. Using immunoblotting we showed that CMP reduced ST8iaII-mediated polysialylation of NCAM. Utilizing a novel HPLC-based assay to quantify polysialylation of a fluorescent acceptor (DMB-DP3), we demonstrated that CMP is a competitive inhibitor of ST8SiaII (Ki = 10 μM). Importantly, we have shown that CMP causes a concentration-dependent reduction in tumour cell-surface polySia expression, with an absence of toxicity. When ST8SiaII-expressing tumour cells (SH-SY5Y and C6-STX) were evaluated in 2D cell migration assays, ST8SiaII inhibition led to significant reductions in migration, while CMP had no effect on cells not expressing ST8SiaII (DLD-1 and C6-WT). The study demonstrates for the first time that a polysialyltransferase inhibitor can modulate migration in ST8SiaII-expressing tumour cells. We conclude that ST8SiaII can be considered a druggable target with the potential for interfering with a critical mechanism in tumour cell dissemination in metastatic cancers.en_US
dc.description.sponsorshipYorkshire Cancer Research; EPSRC; Association for International Cancer Research; Jordanian Government PhD scholarshipen_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073366en_US
dc.rights© 2013 Al-Saraireh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectPolysialic acid; Polysialyltransferase; Cancer; Cell migration; REF 2014en_US
dc.titlePharmacological Inhibition of polysialyltransferase ST8SiaII Modulates Tumour Cell Migrationen_US
dc.status.refereedYesen_US
dc.date.Accepted2013-07-18
dc.typeArticleen_US
dc.type.versionpublished versionen_US
refterms.dateFOA2018-07-25T12:50:30Z


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