PAR2 Serves an Indispensable Role in Controlling PAR4 Oncogenicity: The β-Catenin-p53 Axis
Priyanga Appasamy1, Jeetendra Kumar Nag1, Hodaya Malka1
1Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
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.
Insights
Protease-activated receptor 2 (PAR2) drives cancer growth by cooperating with PAR4. Inhibiting PAR2 signaling blocks PAR4
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.
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