Matriptase Is Involved in ErbB-2-Induced Prostate Cancer Cell Invasion

Deregulation of both ErbB 2 signaling and matriptase activity has been associated with human prostate cancer (PCa) progression In this communication we investigated the roles of both ErbB 2 signaling in matriptase zymogen activation and matriptase m ErbB 2 induced PCa malignancy In a human PCa cell progression model we observed that advanced PCa C 81 LNCaP cells exhibited an aggressive phenotype with increased cell migration and invasion capacity these cells concurrently showed both enhanced ErbB 2 phosphorylation and increased matriptase zymogen activation compared with parental C 33 LNCaP cells Moreover ErbB2 activation both ligand dependent (eg epidermal growth factor treatment) and ligand independent (eg overexpression) was able to induce matriptase zymogen activation in this cell line Inhibition of ErbB 2 activity by either the specific inhibitor AG825 in epidermal growth factor treated C 33 LNCaP cells or ErbB 2 knockdown in C 81 LNCaP cells reduced matriptase activation These observations were confirmed by similar studies using both DU145 and PC3 cells Together these data suggest that ErbB 2 signaling plays an important role in matriptase zymogen activation ErbB-2 enhanced matriptase activation was suppressed by a phosphatidylinositol 3 kinase inhibitor (ie LY294002) but not by a MEK inhibitor (ie PD98059) Suppression of matriptase expression by small hairpin RNA knockdown in ErbB 2 overexpressing LNCaP cells dramatically suppressed cancer cell invasion In summary our data indicate that ErbB-2 signaling via the phosphatidylinositol 3 kinase pathway results m up-regulated matriptase zymogen activity which contributes to PCa cell invasion (Am J Pathol 2010 177 3145-3154 DO! 10 2353/ajpath 2010 100228)