Autocrine proteinase-activated receptor signaling in PC3 prostate cancer cells

Proteinase-activated receptors (PARs) are G protein-coupled receptors (GPCRs) activated by limited N-terminal proteolysis. PARs are highly expressed in many cancer cells, including prostate cancer (PCa), and regulate various aspects of tumor growth and metastasis. Specific activators of PARs in different physiological and pathophysiological contexts remain poorly defined. In this study, we examined the androgen-independent human prostatic cancer cell line PC3 and find the functional expression of PAR1 and PAR2, but not PAR4. Using genetically encoded PAR cleavage biosensors, we showed that PC3 cells secrete proteolytic enzymes that cleave PARs and trigger autocrine signaling. CRISPR/Cas9 targeting of PAR1 and PAR2 combined with microarray analysis revealed genes that are regulated through this autocrine signaling mechanism. We found several genes that are known PCa prognostic factors or biomarker to be differentially expressed in the PAR1-knockout (KO) and PAR2-KO PC3 cells. We further examined PAR1 and PAR2 regulation of PCa cell proliferation and migration and found that absence of PAR1 promotes PC3 cell migration and suppresses cell proliferation, whereas PAR2 deficiency showed opposite effects. Overall, these results demonstrate that autocrine signaling through PARs is an important regulator of PCa cell function.

Automated summary

Proteinase-activated receptors (PARs) in prostate cancer cells regulate tumor growth and metastasis through autocrine signaling. In this study, PAR1 and PAR2 were found to be functional in PC3 cells, while PAR4 was not expressed. The secretion of proteolytic enzymes by PC3 cells triggers cleavage of PARs, leading to autocrine signaling and the regulation of genes related to prostate cancer. PAR1 deficiency promotes cell migration and suppresses cell proliferation, while PAR2 deficiency has the opposite effects.