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Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching
- Source :
- British Journal of Cancer
- Publication Year :
- 2016
- Publisher :
- Nature Publishing Group, 2016.
-
Abstract
- Background: The arachidonic acid metabolite 12(S)-HETE is suspected to enhance metastatic spread by inducing cancer cell- and lymph endothelial cell (LEC) motility. However, the molecular mechanisms leading to 12(S)-HETE-triggered cell migration are still elusive. Methods: To delineate the signalling pathways involved in 12(S)-HETE-mediated migration, inhibitors against RHO and ROCK, and specific siRNAs downregulating 12(S)-HETE receptor (12-HETER) and myosin light chain 2 (MLC2) were used. The breaching of the endothelial barrier was investigated by an assay measuring tumour spheroid-triggered ‘circular chemorepellent-induced defects' (CCIDs), and respective signal transduction was elucidated by western blotting. Results: We provide evidence that 12(S)-HETE phosphorylated (and activated) MLC2, which regulates actin/myosin-based contraction. MLC2 activation was found to be essential for LEC retraction and CCID formation. Furthermore, we show that 12(S)-HETE activated a 12-HETER–RHO–ROCK–MYPT signalling cascade to induce MLC2 function. Conclusions: Signalling via this pathway is described for this metabolite for the first time. This may provide potential targets for the intervention of metastatic colonisation.
- Subjects :
- 0301 basic medicine
Cancer Research
MLC2
Myosin light-chain kinase
Myosin Light Chains
Motility
Biology
Permeability
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
Myosin
Humans
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
Phosphorylation
Receptor
3D-intravasation model
Molecular Diagnostics
Actin
rho-Associated Kinases
Cell migration
12(S)-HETE
Rho Factor
Cell biology
Endothelial stem cell
030104 developmental biology
Oncology
lymph endothelial cell migration
Receptors, Eicosanoid
030220 oncology & carcinogenesis
Immunology
lipids (amino acids, peptides, and proteins)
Signal transduction
Endothelium, Lymphatic
tumour microenvironment
signal transduction
Subjects
Details
- Language :
- English
- ISSN :
- 15321827 and 00070920
- Volume :
- 115
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- British Journal of Cancer
- Accession number :
- edsair.doi.dedup.....b4ca03aad14419d81cbd5d6ccc3056c1