CASK promotes prostate cancer progression via kinase-dependent activation of AKT

Until now, the role of calcium/calmodulin-dependent serine protein kinase (CASK) in prostate cancer (PCa) progression remains unknown. In this study, we investigated the roles of CASK in PCa progression, cell migration, and invasion. We found that CASK is up-regulated in PCa tissues of patients. Lentivirus-based CASK silencing does not affect cell growth or serum-free-induced cell death in PC3 and LNCaP cells, regardless of the presence or absence of TGF-β. CASK silencing decreases cell migration and invasion, either in the absence or presence of TGF-β stimulation. Immunoblotting data indicate that CASK silencing does not alter TGF-β-induced Smad2/3 and ERK phosphorylation but reduces TGF-β-induced AKT phosphorylation. To understand the roles of AKT and CaMK-like activity of CASK in cellular responses in PCa cells, we treated cells with AKT inhibitor and specific kinase inhibitors of CASK (NR162) and CaMKII (KN-93). We found that these agents can inhibit cell invasion and migration. In addition, NR162 and KN-93 also reduce TGF-β-induced AKT phosphorylation. Moreover, the co-immunoprecipitation data indicate the association between CASK and AKT. In HEK293 cells overexpressing system, we further found that CASK can enhance AKT S473 phosphorylation. The tumorigenic effect of CASK is confirmed in the xenograft mouse system. In summary, CASK is a promoter of PCa progression and can enhance PCa cell migration and invasion via kinase-dependent AKT activation independent of TGF-β-induced Smad2/3 and ERK signaling.