Targeting Neuropilin-1 in Prostate Cancer Bone Metastasis

摘要

The role of neuropilin-1 (NRP1) in the progression of human prostate cancer (PCa) remains unclear. This New Investigator Award is to investigate the signaling mechanism and targeting potential of NRP1 in PCa bone metastasis. During the entire period of award performance, we accomplished three major tasks: 1) Molecular mechanism of NRP1 signaling in bone metastatic PCa cells. We elucidated a novel signaling mechanism by which bone metastatic PCa cells acquire survival advantages through the induction of VEGF via a CREB-HIF-1- dependent pathway, which subsequently activates autocrine signaling by inducing NRP1-c-MET signaling and upregulates Mcl-1 expression via Stat3. We identified Mcl-1 as a convergent molecular target of VEGF and PDGF signaling in bone metastatic PCa cells. 2) Clinical significance of NRP1 signaling components in human PCa bone metastasis. We validated the clinical importance of our findings in human PCa bone metastasis. Expression of the key signaling components, including p-CREB, VEGF, NRP1, p-c-MET and Mcl-1, was found to be significantly associated with PCa bone metastasis. 3) Targeting NRP1 signaling in bone metastatic PCa cells. We explored the targeting potential of the NRP1- Mcl-1 signaling pathway in treating PCa bone metastasis. Several strategies (including siRNA, shRNA, monoclonal antibody and small molecule agents) were developed to effectively induce apoptosis and tumor regression in pre-clinical models of PCa metastasis.