MMP1 and PRSS23 induce PAR2 biased agonism in painful oral cancers.

Protease-activated receptor 2 (PAR2) mediates oral cancer pain. Patients with metastatic (N + ) cancers report greater pain. PAR2 is activated by N-terminal proteolytic cleavage. Here we show that proteases encoded by genes overexpressed in N+ cancers from patients with pain (matrix metallopeptidase 1, MMP1 and serine protease 23, PRSS23) elicit protease-specific receptor redistribution (trafficking) and signaling that differs from that promoted by proteases encoded by genes not differentially expressed (transmembrane serine protease matriptase, ST14 and cathepsin S, CTSS). Mixtures of the proteases prepared to model the oral cancer microenvironment revealed that ST14-mediated PAR2 activation predominated at low protease concentrations. At high concentrations, MMP1 and PRSS23 prevailed over the greater potency of ST14. We propose that PAR2 activation in oral N+ cancers from patients with pain is driven by high levels of MMP1 and PRSS23. Our study informs design of signaling and location-specific antagonists to provide more efficacious analgesia.