Role of I-kappa-B Kinases in Prostate Carcinogenesis and the Effect of Their Inhibition on Survival of Prostate Tumors

摘要

The research project was planned to investigate the role of IKB kinases (IKK) and NF-KB in development of prostate cancer (CaP) and explore the possibility that IKK inhibitors can be used in CaP treatment. To reach this goal we employed mouse models and in vitro cell culture systems. We found neither IKK beta nor IKK alpha were required for normal prostate development. However IKK alpha plays an important role in development of advanced CaP particularly in CaP metastasis. IKK alpha links inflammation to CaP metastasis by suppressing expression of the metastasis-suppressor gene maspin in response to RANK signaling. We also found that IKK beta/NF-kB activities in CaP cells were dramatically increased during development of androgen resistance. Deletion of IKK beta in inflammatory cells of the tumor microenvironment significantly reduced androgen-independent CaP formation. Furthermore we found that a putative IKK inhibitor IT-3 could suppress the proliferation of human CaP cells in vitro. Our results suggest an important role for both lKKa and IKK beta in development and progression of CaP and inhibition of one or both of them would be an effective option for treatment of CaP especially for prevention of metastasis and emergence of hormone refractory CaP.