Role of Raf Kinase Inhibitor Protein in Pathophysiology of Prostate Cancer.

Abstract

Raf kinase inhibitor protein (RKIP) is a small, cytosolic protein named for its ability to block Raf-mediated activation of MAPK and ERK. It also block G-protein signaling and NF-κB activation. An in vitro screen to identify genes that regulate prostate cancer (PCa) metastasis revealed that expression of RKIP was decreased in high versus low metastatic PCa cells. Modulation of RKIP expression revealed that it inhibited invasion and loss of RKIP promoted in vitro invasion. Animal studies were used to demonstrate that RKIP could inhibit PCa metastasis from orthotopically injected tumor cells without an effect on primary tumor growth. Taken together, these results indicated RKIP acted as a PCa metastasis suppressor gene. Evaluation of RKIP expression in clinical cases of PCa revealed that RKIP expression was moderate to high in non-neoplastic prostate, low in 50% of primary prostate cancers, and absent to low in the majority of metastases. Furthermore, low RKIP expression in primary prostate tumors was predictive of early tumor recurrence. Loss of RKIP was shown to induce resistance to radiation in PCa cells in vitro and in an in vivo murine model. Taken together, these studies indicate that RKIP plays multiple roles in PCa pathophysiology, suggesting that a method to increase RKIP expression in PCa may have therapeutic benefits.