PAR2 Serves an Indispensable Role in Controlling PAR4 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 PAR₂ is dominant over PAR₄ oncogene in cancer. We performed a knockdown of <i>Par2</i>/<i>f2rl1</i> and expressed C-terminally truncated PAR₂ (TrPAR₂), incapable of inducing signaling, to assess the impact of PAR₂ on PAR₄ oncogenic function by β-catenin stabilization assessment, immunoprecipitation, and xenograft tumor generation in <i>Nude</i>/<i>Nude</i> mice. PAR₂ and PAR₄ act together to promote tumor generation. Knockdown <i>Par2</i> and TrPAR₂ inhibited the PAR₂ and PAR₄-induced β-catenin levels, nuclear dishevelled 1(DVL1), and TOP<i>flash</i> reporter activity. Likewise, PAR₂ and PAR₄-induced invasion and migration were inhibited when <i>Par2</i> was knocked down or in the presence of TrPAR₂. PAR cyclic (4-4) [P<i>c</i>(4-4)], a PAR-based compound directed toward the PAR pleckstrin homology (PH)-binding site, effectively inhibited PAR₂ oncogenic activity. P<i>c</i>(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 PAR₂ signaling, the PAR₄ pro-tumor functions are significantly inhibited. P<i>c</i>(4-4) inhibits PAR₂ acting via the modification of <i>wt</i> p53, thus offering a powerful drug measure for fighting cancer.