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

Area of Science:

• Oncology
• Molecular Biology
• G-protein-coupled receptor signaling

Background:

• G-protein-coupled receptors (GPCRs) play a role in cancer, but GPCR-targeted therapies are uncommon.
• Protease-activated receptors (PARs), a GPCR subgroup, include PAR1-4. PAR2's role in cancer, particularly its interaction with PAR4, requires further elucidation.

Purpose of the Study:

• To investigate the dominant role of PAR2 over PAR4 in cancer.
• To assess the impact of PAR2 on PAR4's oncogenic function.
• To evaluate the therapeutic potential of targeting PAR2 signaling.

Main Methods:

• Gene knockdown of PAR2 (f2rl1) and expression of a non-signaling truncated PAR2 (TrPAR2).
• Assessment of beta-catenin stabilization, immunoprecipitation, and xenograft tumor formation in nude mice.
• Evaluation of PAR2/PAR4-induced signaling pathways, including DVL1 and TOPflash reporter activity.
• Analysis of cell invasion, migration, and the effect of a PAR2-specific inhibitor, Pc(4-4).

Main Results:

• PAR2 and PAR4 collaborate to promote tumor generation.
• PAR2 knockdown or TrPAR2 expression inhibited PAR2/PAR4-induced beta-catenin levels, nuclear DVL1, and TOPflash activity.
• PAR2 and PAR4-mediated invasion and migration were suppressed by PAR2 knockdown or TrPAR2.
• The PAR2 inhibitor Pc(4-4) effectively inhibited PAR2 oncogenic activity by increasing p53 and p21 levels and activating caspase-3.
• PAR4 pro-tumor functions were significantly inhibited in the absence of PAR2 signaling.

Conclusions:

• PAR2 signaling is crucial for PAR4's pro-tumorigenic functions in cancer.
• PAR2 acts dominantly over PAR4 in driving oncogenesis.
• The PAR2 inhibitor Pc(4-4) demonstrates therapeutic potential by targeting PAR2 signaling, modulating p53, and inhibiting tumor growth.