PRSS3/mesotrypsin is a therapeutic target for metastatic prostate cancer.

PRSS3/mesotrypsin is an atypical isoform of trypsin that has been associated with breast, lung, and pancreatic cancer cell malignancy. In analyses of open source transcriptional microarray data, we find that PRSS3 expression is upregulated in metastatic prostate cancer tissue, and that expression of PRSS3 in primary prostate tumors is prognostic of systemic progression following prostatectomy. Using a mouse orthotopic model with bioluminescent imaging, we show that PRSS3/mesotrypsin is critical for prostate cancer metastasis. Silencing of PRSS3 inhibits anchorage-independent growth of prostate cancer cells in soft agar assays, and suppresses invasiveness in Matrigel transwell assays and three-dimensional (3D) cell culture models. We further show that treatment with recombinant mesotrypsin directly promotes an invasive cellular phenotype in prostate cancer cells and find that these effects are specific and require the proteolytic activity of mesotrypsin, because neither cationic trypsin nor a mesotrypsin mutant lacking activity can drive the invasive phenotype. Finally, we show that a newly developed, potent inhibitor of mesotrypsin activity can suppress prostate cancer cell invasion to a similar extent as PRSS3 gene silencing. This study defines mesotrypsin as an important mediator of prostate cancer progression and metastasis, and suggests that inhibition of mesotrypsin activity may provide a novel modality for prostate cancer treatment.