Enhancement role of host 12/15-lipoxygenase in melanoma progression
Journal
European Journal of Cancer
Journal Volume
49
Journal Issue
12
Pages
2747-2759
Date Issued
2013
Author(s)
Abstract
12/15-Lipoxygenase (12/15-LOX) is a non-haeme iron-containing dioxygenase that forms 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) or 15(S)-HETE. Several biological mediators including cytokines, growth factors and lipid metabolites released during tumour cell-endothelial cell adhesion are associated with malignant tumour progression. Here we found that HETEs released from the host organ played a critical role in tumour metastasis. Intravenous injection of B16F10 melanoma cells caused lung nodule formation, which was markedly attenuated in 12/15-LOX null mice. Co-injection of melanoma cells with 12(S)-HETE increased the lung homing activity of B16F10 melanoma cells. In vitro studies showed that 12(S)-HETE and 15(S)-HETE treatment resulted in a concentration-dependent increase of adhesion of B16F10 cells on collagen or fibronectin. The melanoma cell adhesion was then evaluated in pulmonary primary cell culture isolated from wild-type (WT) and 12/15-LOX knockout (KO) mice. It was found that the adhesion of melanoma cells on the epithelial cells isolated from 12/15-LOX null mice was reduced in comparison with those isolated from WT mice. Treatment of 12(S)-HETE increased the pFAK in melanoma cells adhering on collagen-coated slide. The enhancement of adherence elicited by 12(S)-HETE in B16F10 cells could be antagonised by focal adhesion kinase (FAK) inhibitor 14 (FAK inhibitor) or PD98059 (extracellular signal-regulated kinase (ERK) inhibitor). 12(S)-HETE increased the phosphorylation of FAK and ERK in adhering melanoma cells. The FAK phosphorylation induced by 12(S)-HETE was further inhibited by PD98059, indicating that FAK is the downstream target of ERK. The adhesion and lung metastasis of human melanoma cells of C32 in NOD/SCID mice were also potentiated by co-treatment with 12(S)-HETE. These results demonstrate that 12(S)-HETE/15(S)-HETE activates ERK and FAK signalling pathways, thereby upregulates the adhesion and metastatic potential of melanoma cells. The endogenous release of 12(S)-HETE/15(S)-HETE in the host organ may affect the metastatic potential of melanoma. ? 2013 Elsevier Ltd. All rights reserved.
SDGs
Other Subjects
2 (2 amino 3 methoxyphenyl)chromone; arachidonate 12 lipoxygenase; arachidonate 15 lipoxygenase; fibronectin; focal adhesion kinase inhibitor; hydroxyicosatetraenoic acid; mitogen activated protein kinase inhibitor; animal behavior; animal cell; animal experiment; animal model; article; cell adhesion; cell isolation; concentration (parameters); disease course; epithelium cell; human; human cell; in vitro study; knockout mouse; lung metastasis; lung nodule; male; melanoma cell; metastasis potential; mouse; nonhuman; primary cell culture; priority journal; protein phosphorylation; SCID mouse; wild type; 12/15-Lipoxygenase; Cell adhesion; HETE; Melanoma; 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Blotting, Western; Cell Adhesion; Cell Line, Tumor; Collagen; Disease Progression; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Fibronectins; Focal Adhesion Protein-Tyrosine Kinases; Humans; Hydroxyeicosatetraenoic Acids; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Signal Transduction; Transplantation, Heterologous; Tumor Cells, Cultured
Type
journal article