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.
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.
Bergelin
N
N
Department of Biology, Abo Akademi University, BioCity, Tykistökatu 6, 20520 Turku, Finland.
Blom
T
T
Heikkilä
J
J
Löf
C
C
Alam
C
C
Balthasar
S
S
Slotte
J P
JP
Hinkkanen
A
A
Törnquist
K
K
D019898:Autocrine Communication / Q000235:genetics / Q000502:physiology; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D008246:Lysophospholipids / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009857:Oncogenes / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000502:physiology*; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology*; D014162:Transfection; D000099157:Sphingosine Kinase
D008246:Lysophospholipids; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017853:Phosphotransferases (Alcohol Group Acceptor); D051571:Protein Kinase C-alpha; D034741:RNA, Small Interfering; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate