12(S)-HETE, pleiotropic functions, multiple signaling pathways.
The arachidonic acid metabolite of 12 lipoxygenase, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) promotes metastatic behavior of tumor cells (1). In this study we set out to identify 12(S)-HETE stimulated signaling pathways, and their contribution to cellular functions in A431 epidermoid carcinoma. 1) 12(S)-HETE signaling involves extracellular-regulated protein kinase (ERK1/2), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3 kinase) and Src kinase. 2) 12(S)-HETE stimulates cell migration on laminin, which is eliminated by PKC and PI3 kinase inhibitors, reduced by 50% with Src inhibitor, but unaffected by inhibition of ERK1/2. 3) 12(S)-HETE stimulated spreading on fibronectin relies on ERK1/2 and PI3 kinase activities, but not on PKC or Src. 4) Focal adhesion kinase, a key organizer of focal adhesions, is tyrosine phosphorylated in response of 12(S)-HETE treatment, which requires Src, but not PKC, PI3 kinase or ERK1/2 activity. 5) Inhibition of 12 lipoxygenase leads to apoptosis in serum starved A431 cells. 12(S)-HETE stimulated p90Rsk and Akt, key players in an ERK and a PI3 kinase (respectively) dependent anti apoptotic pathways.
Szekeres
Charles K
CK
Dept. of Radiation Oncology, Wayne State University, Karmanos Cancer Institute, Detroit, MI, USA.
Trikha
Mohit
M
Honn
Kenneth V
KV
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000494:pharmacology* / Q000502:physiology*; D002227:Carbazoles / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; C081021:Go 6976; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases