title: Enhanced expression of transferrin receptor 1 contributes to oncogenic signalling by sphingosine kinase 1.
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.
authors.affiliation: 1] Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, SA, Australia [2] School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia.
authors.forename: D H
authors.initials: DH
authors.lastname: Pham
authors.affiliation: Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, SA, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Powell
authors.affiliation: Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, SA, Australia.
authors.forename: B L
authors.initials: BL
authors.lastname: Gliddon
authors.affiliation: Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, SA, Australia.
authors.forename: P A B
authors.initials: PA
authors.lastname: Moretti
authors.affiliation: 1] Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, SA, Australia [2] School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Tsykin
authors.affiliation: Adelaide Microarray Facility, SA Pathology, Frome Road, Adelaide, SA, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Van der Hoek
authors.affiliation: Adelaide Microarray Facility, SA Pathology, Frome Road, Adelaide, SA, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Kenyon
authors.affiliation: 1] Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, SA, Australia [2] School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia [3] School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA, Australia.
authors.forename: G J
authors.initials: GJ
authors.lastname: Goodall
authors.affiliation: 1] Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, SA, Australia [2] School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia [3] School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA, Australia.
authors.forename: S M
authors.initials: SM
authors.lastname: Pitson
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D009369:Neoplasms / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D011990:Receptors, Transferrin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D000099157:Sphingosine Kinase
chemical_list: D015703:Antigens, CD; D017853:Phosphotransferases (Alcohol Group Acceptor); D034741:RNA, Small Interfering; D011990:Receptors, Transferrin; D000099157:Sphingosine Kinase; C068126:CD71 antigen