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Sphingosine kinase as an oncogene: autocrine sphingosine 1-phosphate modulates ML-1 thyroid carcinoma cell migration by a mechanism dependent on protein kinase C-alpha and ERK1/2

Authors

N. Bergelin

T. Blom

J.

C.

S. Balthasar

J.P. Slotte

A. Hinkkanen

K.



Abstract

Sphingosine 1-phosphate (S1P) induces migration of the human thyroid follicular carcinoma cell line ML-1 by activation of S1P(1) and S1P(3) receptors, G(i) proteins, and the phosphatidylinositol 3-kinase-Akt pathway. Because sphingosine kinase isoform 1 (SK) recently has been implicated as an oncogene in various cancer cell systems, we investigated the functions of SK in the migration, proliferation and adhesion of the ML-1 cell line. SK overexpressing ML-1 cells show an enhanced secretion of S1P, which can be attenuated, by inhibiting SK activity and a multidrug-resistant transport protein (ATP-binding cassette transporter). Furthermore, overexpression of SK enhances serum-induced migration of ML-1 cells, which can be attenuated by blocking ATP-binding cassette transporter and SK, suggesting that the migration is mediated by autocrine signaling through secretion of S1P. Inhibition of protein kinase C alpha, with both small interfering RNA (siRNA) and small molecular inhibitors attenuates migration in SK overexpressing cells. In addition, SK-overexpressing cells show an impaired adhesion, slower cell growth, and an up-regulation of ERK1/2 phosphorylation, as compared with cells expressing a dominant-negative SK. Taken together, we present evidence suggesting that SK enhances migration of ML-1 cells by an autocrine mechanism and that the S1P-evoked migration is dependent on protein kinase C alpha, ERK1/2, and SK.

Citation

Bergelin, N., Blom, T., Heikkilä, J., Löf, C., Alam, C., Balthasar, S., …Törnquist, K. (2009). Sphingosine kinase as an oncogene: autocrine sphingosine 1-phosphate modulates ML-1 thyroid carcinoma cell migration by a mechanism dependent on protein kinase C-alpha and ERK1/2. Endocrinology, 150(5), 2055-2063. https://doi.org/10.1210/en.2008-0625

Journal Article Type Article
Acceptance Date Dec 2, 2008
Publication Date 2009-05
Deposit Date May 26, 2022
Journal Endocrinology
Print ISSN 0013-7227
Publisher Endocrine Society
Peer Reviewed Peer Reviewed
Volume 150
Issue 5
Pages 2055-2063
DOI https://doi.org/10.1210/en.2008-0625
Public URL http://researchrepository.napier.ac.uk/Output/2870015
Publisher URL http://intl-endo.endojournals.org/cgi/content/full/150/5/2055