Raf kinase inhibitor protein: a prostate cancer metastasis suppressor gene

Abstract

Defining the mechanisms that confer metastatic ability on cancer cells is an important goal towards prevention of metastasis. A gene array screen between a non-metastatic prostate cancer cell and its metastatic derivative line revealed decreased expression of Raf kinase inhibitor protein (RKIP) in the metastatic cell line. This finding is consistent with the possibility that loss of RKIP is associated with metastasis. RKIP is expressed in many tissues including brain, lung, and liver. RKIP blocks Raf-induced phosphorylation of MEK. In addition to its modulation of Raf signaling, RKIP modulates both G-protein signaling and NF-kappaB activity. The impact that RKIP has on multiple signaling pathways grants it the ability to play a role in several cellular functions including membrane biosynthesis, spermatogenesis, and neural signaling. Novel cellular functions for RKIP continue to be identified, several of which contribute to cancer biology. For example, RKIP promotes apoptosis of cancer cells, which suggests that loss of RKIP in cancer will protect cancer cells against cell death. Additionally, restoration of RKIP expression ina metastatic prostate cancer cell line does not effect primary tumor growth, but it does inhibit prostate cancer metastasis. These parameters identify RKIP as a metastasis suppressor gene, which suggest that it or proteins it interacts with are putative molecular targets to control metastasis. These findings are supported by the observation that RKIP expression is decreased in metastases of prostate cancer patients, compared to normal prostate or the primary prostate tumor. In this review, RKIP biology and its role in cancer will be described.