PAR(2) Serves an Indispensable Role in Controlling PAR(4) Oncogenicity: The β-Catenin-p53 Axis.

Although the role of G-protein-coupled receptors (GPCRs) in cancer is acknowledged, GPCR-based cancer therapy is rare. Mammalian protease-activated receptors (PARs), a sub-group of GPCRs, comprise four family members, termed PAR(1-4). Here, we demonstrate that PAR(2) is dominant over PAR(4) oncogene in cancer. We performed a knockdown of Par2/f2rl1 and expressed C-terminally truncated PAR(2) (TrPAR(2)), incapable of inducing signaling, to assess the impact of PAR(2) on PAR(4) oncogenic function by β-catenin stabilization assessment, immunoprecipitation, and xenograft tumor generation in Nude/Nude mice. PAR(2) and PAR(4) act together to promote tumor generation. Knockdown Par2 and TrPAR(2) inhibited the PAR(2) and PAR(4)-induced β-catenin levels, nuclear dishevelled 1(DVL1), and TOPflash reporter activity. Likewise, PAR(2) and PAR(4)-induced invasion and migration were inhibited when Par2 was knocked down or in the presence of TrPAR(2). PAR cyclic (4-4) [Pc(4-4)], a PAR-based compound directed toward the PAR pleckstrin homology (PH)-binding site, effectively inhibited PAR(2) oncogenic activity. Pc(4-4) inhibition is mediated via the increase in p53 level and the up-regulation of p21 as caspase-3 as well. Overall, we showed that in the absence of PAR(2) signaling, the PAR(4) pro-tumor functions are significantly inhibited. Pc(4-4) inhibits PAR(2) acting via the modification of wt p53, thus offering a powerful drug measure for fighting cancer.