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

D. H. Pham, J. A. Powell, B. L. Gliddon, P. A B Moretti, A. Tsykin, M. Van der Hoek, R. Kenyon, G. J. Goodall, S. M. Pitson

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

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, S1P 2. 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 S1P 2. Together these findings suggest that TFR1 has an important role in SK1-mediated oncogenesis.

Original languageEnglish
Pages (from-to)5559-5568
Number of pages10
JournalOncogene
Volume33
Issue number48
DOIs
Publication statusPublished - 27 Nov 2014
Externally publishedYes

Keywords

  • DNA microarray
  • expression profiling
  • neoplastic transformation
  • sphingosine kinase
  • transferrin receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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