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

Bergelin, N.; Blom, T.; Heikkil�, J.; L�f, C.; Alam, C.; Balthasar, S.; Slotte, J.P.; Hinkkanen, A.; T�rnquist, 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.

• 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