# PAR2 Serves an Indispensable Role in Controlling PAR4 Oncogenicity: The β-Catenin–p53 Axis

## TL;DR

This study shows that PAR2 is essential for PAR4's cancer-promoting effects, and a compound called Pc(4-4) can inhibit this process by boosting p53 activity.

## Contribution

The study reveals a novel role of PAR2 in modulating PAR4 oncogenicity through the β-catenin–p53 axis and identifies Pc(4-4) as a potential anti-cancer drug.

## Key findings

- PAR2 knockdown or TrPAR2 expression inhibits PAR4-induced β-catenin stabilization and tumor growth.
- Pc(4-4) inhibits PAR2 activity by increasing p53 and p21 levels, reducing cancer cell invasion and migration.
- PAR2 signaling is indispensable for PAR4's pro-tumor functions.

## Abstract

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 PAR1–4. Here, we demonstrate that PAR2 is dominant over PAR4 oncogene in cancer. We performed a knockdown of Par2/f2rl1 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 Nude/Nude mice. PAR2 and PAR4 act together to promote tumor generation. Knockdown Par2 and TrPAR2 inhibited the PAR2 and PAR4-induced β-catenin levels, nuclear dishevelled 1(DVL1), and TOPflash reporter activity. Likewise, PAR2 and PAR4-induced invasion and migration were inhibited when Par2 was knocked down or in the presence of TrPAR2. PAR cyclic (4-4) [Pc(4-4)], a PAR-based compound directed toward the PAR pleckstrin homology (PH)-binding site, effectively inhibited PAR2 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 PAR2 signaling, the PAR4 pro-tumor functions are significantly inhibited. Pc(4-4) inhibits PAR2 acting via the modification of wt p53, thus offering a powerful drug measure for fighting cancer.