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Type: Journal article
Title: Enhanced expression of transferrin receptor 1 contributes to oncogenic signalling by sphingosine kinase 1
Author: Pham, D.
Powell, J.
Gliddon, B.
Moretti, P.
Tsykin, A.
Van der Hoek, M.
Kenyon, R.
Goodall, G.
Pitson, S.
Citation: Oncogene, 2014; 33(48):5559-5568
Publisher: Nature Publishing Group
Issue Date: 2014
ISSN: 0950-9232
Statement of
D 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
Abstract: Sphingosine 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.
Keywords: Expression profiling
DNA microarray
neoplastic transformation
sphingosine kinase
transferrin receptor
Description: Advance online publication 25 November 2013
Rights: © 2013 Macmillan Publishers Limited. All Rights Reserved.
DOI: 10.1038/onc.2013.502
Grant ID: 508098
Appears in Collections:Aurora harvest 4
Molecular and Biomedical Science publications

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