Enhanced expression of transferrin receptor 1 contributes to oncogenic signalling by sphingosine kinase 1
Date
2014
Authors
Pham, D.
Powell, J.
Gliddon, B.
Moretti, P.
Tsykin, A.
Van der Hoek, M.
Kenyon, R.
Goodall, G.
Pitson, S.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Oncogene, 2014; 33(48):5559-5568
Statement of Responsibility
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
Conference Name
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.
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Dissertation Note
Provenance
Description
Advance online publication 25 November 2013
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© 2013 Macmillan Publishers Limited. All Rights Reserved.