Metastasis suppressor genes: a role for raf kinase inhibitor protein (RKIP)

The metastatic cascade is a complicated process that involves many steps from gain of the metastatic phenotype in the primary tumor cells through establishment of macroscopic tumor at the distant target organ. A group of genes, termed metastasis suppressor genes (MSG), encode for proteins that inhibit various steps of the metastatic cascade. Accordingly, loss of MSG promotes the metastatic phenotype. Although several MSG have been identified, the mechanisms through which they enhance metastasis are not clearly defined. Gene array analysis of a low metastatic LNCaP prostate cancer cell line compared to its highly metastatic derivative C4-2B prostate cancer cell line revealed decreased expression of raf kinase inhibitor protein (RKIP) in the C4-2B cell line. RKIP blocks the activation of several signaling pathways including MEK, G-proteins and NFkappaB. Immunohistochemical analysis of prostate cancer primary tumors and metastases revealed that RKIP protein expression was decreased in metastases. Restoration of RKIP expression in the C4-2B cell line diminished metastasis in a murine model. These results demonstrate that RKIP is a MSG. Loss of RKIP enhanced both angiogenesis and vascular invasion, and protected against apoptosis. These findings suggest that targeting the RKIP pathway may diminish the metastatic cascade. However, challenges exist as to the best method to target RKIP expression. Restoration of RKIP expression in all cancer cells in vivo is challenging. A plausible strategy is to use small molecules that target proteins in signaling pathways that are dysregulated due to loss of RKIP.