Inhibition of Prostate Cancer Skeletal Metastases by Targeting Cathepsin K

The prostate cancer (PCa) metastasis processes are facilitated by proteolytic cascade involving cathepsin K (CatK). CatK expression level is higher in PCa bone metastatic sites than primary tumor or normal prostate tissues. The role of CatK in PCa skeletal metastasis, however, is not known. We first confirmed the expression of CatK in LNCaP, C4-2B, and PC3 PCa cell lines. Then, we observed the inhibitory effect of CatK inhibitor on the PCa cell invasion suggesting the role of CaK in PCa tumor invasion. Finally, we injected C4-2B cells into the tibiae of SCID mice and then the animals received either vehicle or Cat K inhibitor for 8 weeks either at the time of tumor cells injection (tumor establishment model) or 4 weeks after tumor cells were injected (tumor progression model). In the tumor establishment model, CatK inhibitor significantly prevented the establishment of mixed osteolytic/osteoblastic tibial tumors as were observed in vehicle-treated animals. In the progression model, CatK inhibitor diminished tumor-induced bone lesions. We conclude that CatK inhibitor is an effective drug to prevent the establishment and diminish progression of PCa growth in bone. The overall goal of this project is to identify a clinically relevant strategy to inhibit PCa skeletal metastasis.