Abstract
Protease activated receptors (PARs) are G-protein coupled receptors that are activated by an unique proteolytic mechanism. These receptors play crucial roles in hemostasis and thrombosis but also in inflammation and vascular development. PARs have also been implicated in tumor progression, invasion and metastasis. In this study, we investigated expression and signaling of PAR1 in nonmalignant pleural mesothelial (Met-5A) and malignant pleural mesothelioma (NCI-H28) cells. We found that the expression level of PAR1 was markedly higher in NCI-H28 cells compared to Met-5A and human primary mesothelial cells. Other three malignant pleural mesothelioma cell lines, i.e. REN, Ist-Mes2, and Mero-14, did not show any significant PAR1 over-expression compared to Met-5A cell line. Thrombin and PAR1 activating peptides enhanced Met-5A and NCI-H28 cell proliferation but in NCI-H28 cells higher thrombin concentrations were required to obtain the same proliferation increase. Similarly, thrombin caused extracellular signal-regulated kinase 1/2 activation in both cell lines but NCI-H28 cells responded at higher agonist concentrations. We also determined that PAR1 signaling through Gq and G12/13 proteins is severely altered in NCI-H28 cells compared to Met-5A cells. On the contrary, PAR1 signaling through Gi proteins was persistently maintained in NCI-H28 cells. Furthermore, we demonstrated a reduction of cell surface PAR1 expression in NCI-H28 and malignant pleural mesothelioma REN cells. Thus, our results provide evidences for dysfunctional PAR1 signaling in NCI-H28 cells together with reduced plasma membrane localization. The role of PAR1 in mesothelioma progression is just emerging and our observations can promote further investigations focused on this G-protein coupled receptor.
Highlights
Malignant mesothelioma (MM) is a relatively rare but highly aggressive neoplasm arising from mesothelial cells on the serosal surfaces of the pleural, peritoneal and pericardial cavities
The chemokine CXL12 and its target receptor CXCR4 which belongs to the large family of seven-transmembrane Gprotein coupled receptors (GPCRs), have been found to be highly expressed in malignant pleural mesothelioma (MPM) cell lines and tumor tissues suggesting they can be involved in tumor progression and survival [2]
We decided to investigate expression and signaling of PAR1 in human pleural mesothelial and MPM cells to evaluate the possible role of this receptor in mesothelioma cell proliferation
Summary
Malignant mesothelioma (MM) is a relatively rare but highly aggressive neoplasm arising from mesothelial cells on the serosal surfaces of the pleural, peritoneal and pericardial cavities. The chemokine CXL12 and its target receptor CXCR4 which belongs to the large family of seven-transmembrane Gprotein coupled receptors (GPCRs), have been found to be highly expressed in malignant pleural mesothelioma (MPM) cell lines and tumor tissues suggesting they can be involved in tumor progression and survival [2]. Among GPCRs, PARs are a subset which have a unique mechanism of activation. They are activated enzymatically through proteolysis by enzymes of the serine protease family [5]. There are four PARs encoded by distinct genes in the mammalian genome The prototype of this GPCR subfamily is PAR1 which transmits cellular response to thrombin [6,7]. Activated PAR1 couples to multiple heterotrimeric Gprotein subtypes including Gi, Gq and G12/13 [11,12]
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