Enhanced expression of transferrin receptor 1 contributes to oncogenic signalling by sphingosine kinase 1

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dc.contributor.authorPham, D.
dc.contributor.authorPowell, J.
dc.contributor.authorGliddon, B.
dc.contributor.authorMoretti, P.
dc.contributor.authorTsykin, A.
dc.contributor.authorVan der Hoek, M.
dc.contributor.authorKenyon, R.
dc.contributor.authorGoodall, G.
dc.contributor.authorPitson, S.
dc.date.issued2014
dc.descriptionAdvance online publication 25 November 2013
dc.description.abstractSphingosine kinase 1 (SK1) is a lipid kinase that catalyses the formation of sphingosine-1-phosphate (S1P). Considerable evidence has implicated elevated cellular SK1 in tumour development, progression and disease severity. In particular, SK1 has been shown to enhance cell survival and proliferation and induce neoplastic transformation. Although S1P has been found to have both cell-surface G-protein-coupled receptors and intracellular targets, the specific downstream pathways mediating oncogenic signalling by SK1 remain poorly defined. Here, using a gene expression array approach, we have demonstrated a novel mechanism whereby SK1 regulates cell survival, proliferation and neoplastic transformation through enhancing expression of transferrin receptor 1 (TFR1). We showed that elevated levels of SK1 enhanced total as well as cell-surface TFR1 expression, resulting in increased transferrin uptake into cells. Notably, we also found that SK1 activation and localization to the plasma membrane, which are critical for its oncogenic effects, are necessary for regulation of TFR1 expression specifically through engagement of the S1P G-protein coupled receptor, S1P2. Furthermore, we showed that blocking TFR1 function with a neutralizing antibody inhibits SK1-induced cell proliferation, survival and neoplastic transformation of NIH3T3 fibroblasts. Similar effects were observed following antagonism of S1P2. Together these findings suggest that TFR1 has an important role in SK1-mediated oncogenesis.
dc.description.statementofresponsibilityD H Pham, J A Powell, B L Gliddon, P A B Moretti, A Tsykin, M Van der Hoek, R Kenyon, G J Goodall and S M Pitson
dc.identifier.citationOncogene, 2014; 33(48):5559-5568
dc.identifier.doi10.1038/onc.2013.502
dc.identifier.issn0950-9232
dc.identifier.issn1476-5594
dc.identifier.orcidPham, D. [0000-0003-0664-4133]
dc.identifier.orcidGoodall, G. [0000-0003-1294-0692]
dc.identifier.orcidPitson, S. [0000-0002-9527-2740]
dc.identifier.urihttp://hdl.handle.net/2440/82919
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.grant508098
dc.relation.grant1042589
dc.rights© 2013 Macmillan Publishers Limited. All Rights Reserved.
dc.source.urihttps://doi.org/10.1038/onc.2013.502
dc.subjectExpression profiling
dc.subjectDNA microarray
dc.subjectneoplastic transformation
dc.subjectsphingosine kinase
dc.subjecttransferrin receptor
dc.titleEnhanced expression of transferrin receptor 1 contributes to oncogenic signalling by sphingosine kinase 1
dc.typeJournal article
pubs.publication-statusPublished

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