Emerging Roles of PAR-1 and PAFR in Melanoma Metastasis

Melanoma growth, angiogenesis and metastatic progression are strongly promoted by the inflammatory tumor microenvironment due to high levels of cytokine and chemokine secretion by the recruited inflammatory and stromal cells. In addition, platelets and molecular components of procoagulant pathways have been recently emerging as critical players of tumor growth and metastasis. In particular, thrombin, through the activity of its receptor protease-activated receptor-1 (PAR-1), regulates tumor cell adhesion to platelets and endothelial cells, stimulates tumor angiogenesis, and promotes tumor growth and metastasis. Notably, in many tumor types including melanoma, PAR-1 expression directly correlates with their metastatic phenotype and is directly responsible for the expression of interleukin-8, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor, platelet-derived growth factor, and integrins. Another proinflammatory receptor–ligand pair, platelet-activating factor (PAF) and its receptor (PAFR), have been shown to act as important modulators of tumor cell adhesion to endothelial cells, angiogenesis, tumor growth and metastasis. PAF is a bioactive lipid produced by a variety of cells from membrane glycerophospholipids in the same reaction that releases arachidonic acid, and can be secreted by platelets, inflammatory cells, keratinocytes and endothelial cells. We have demonstrated that in metastatic melanoma cells, PAF stimulates the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), which results in overexpression of MMP-2 and membrane type 1-MMP (membrane type 1-MMP). Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that metastatic melanoma cells are better equipped than their non-metastatic counterparts to respond to PAF within the tumor microenvironment. The evidence supporting the hypothesis that the two G-protein coupled receptors, PAR-1 and PAFR, contribute to the acquisition of the metastatic phenotype of melanoma is presented and discussed

Impact of inactivity and exercise on the vasculature in humans

The effects of inactivity and exercise training on established and novel cardiovascular risk factors are relatively modest and do not account for the impact of inactivity and exercise on vascular risk. We examine evidence that inactivity and exercise have direct effects on both vasculature function and structure in humans. Physical deconditioning is associated with enhanced vasoconstrictor tone and has profound and rapid effects on arterial remodelling in both large and smaller arteries. Evidence for an effect of deconditioning on vasodilator function is less consistent. Studies of the impact of exercise training suggest that both functional and structural remodelling adaptations occur and that the magnitude and time-course of these changes depends upon training duration and intensity and the vessel beds involved. Inactivity and exercise have direct “vascular deconditioning and conditioning” effects which likely modify cardiovascular risk

The biological activity of acetylated sphingosylphosphorylcholine derivatives

Taking into account their stereochemical similarity with 1-O-alkyl-2-acetyl-sn-glycerol-3-phosphorylcholine (PAF), which is known to exhibit a diverse spectrum of biological actions, including platelet aggregating and glycogenolytic activity, the acetylated derivatives of sphingosylphosphorylcholine and sphingomyelin were synthesized and tested for their ability to promote washed rabbit platelet aggregation and glycogenolysis in Tetrahymena pyriformis cells. Sphingomyelin (SPM) and sphingosylphosphorylcholine (SPC) were subjected to acetylation, following chromatographic purification and physicochemical characterization. The synthesized compounds N-acetyl, O-acetyl SPC (NAc, OAc SPC), N-acetyl SPC (NAc SPC) and O-acetyl SPM (OAc, SPM) were tested far their biological activity in the washed rabbit platelets and washed Tetrahymena pyriformis cell systems. These derivatives induced [H-3] serotonin and ATP release and a monophasic aggregation of washed rabbit platelets in the concentration range 10(-8)-10(-6) M, However, authentic PAF-induced washed rabbit platelet aggregation was inhibited at higher concentrations of the acetylated sphingophospholipid compounds (> 10(-6) M) and by the PAF-specific receptor(s) antagonists kadsurenone and triazolam. Platelet desensitization and crossed desensitization experiments with authentic PAF and the acetylated sphingophospholipids, suggested interaction with the same receptor(s) as PAF and different from the ADP or thrombin receptor. The involvement of calmodulin and protein kinase C in the biological activity of the prepared analogues was also demonstrated. Besides their action on rabbit platelets, the PAF-like activity of the acetylated sphingophospholipids was also demonstrated in a platelet-independent system, by showing that they stimulate glycogenolysis in washed Tetrahymena pyriformis cells. These observations indicate that a new class of compounds with PAF-like activity were synthesized, but their role in the cellular metabolism remains to be shown. The existence of acetylated sphingophospholipids with PAF-like activity has so far been reported only in Urtica dioica