“Dysfunctional PAR1 signaling in the malignant mesothelioma cell line, NCI-H28”

The aim of this study was to investigate PAR1 expression levels, signaling and mitogenic effects in nonmalignant mesothelial (Met-5A) and MM cells (NCI-H28). In this MM cell line, a homozygous deletion of the β-catenin gene (CTNNB1) has been demonstrated (Shigemitsu et al., 2001) while thrombomodulin (TM) , a natural anticoagulant, appears to be silenced by an epigenetic mechanism (Nocchi et al., 2011). Therefore, we considered quite intriguing to study PAR1 expression and signaling in this cell line and correlate our findings to the known genetic and epigenetic alterations. Our study indicates that the expression levels of both PAR1 mRNA and protein are increased in NCI-H28 cells but more important, receptor signaling to down-stream effectors is rather dysfunctional. In fact, the only signaling pathway which is fully maintained is that through Gi proteins while those through G12/13 and Gq are either reduced or abolished. Whereas the lack of thrombomodulin on plasmamembrane can alter PAR1 activation the β-catenin deficiency on the E-cadherin/catenin complexes at cell junctions can interfere with caveolin-1 localization consequently with PAR1 localization and proper signaling to Gq and G12/13.