The Role of RKIP in the Regulation of EMT in the Tumor Microenvironment

SIMPLE SUMMARY: Raf kinase inhibitor protein (RKIP) expression in cancer cells is significantly reduced and promoting cancer cells growth and invasiveness. Overexpresssion of RKIP has been reported to mediate pleiotropic anti-cancer activities including the inhibition of survival signaling pathways, sensitization to cell death by cytotoxic drugs, inhibition of invasion, EMT and metastasis. The molecular mechanism by which RKIP inhibits EMT is not clear. In this review, we have examined how RKIP inhibits the selected EMT gene products (Snail, vimentin, N-cadherin, laminin alpha) and found that it involves signaling cross-talks between RKIP and each of the EMT gene products. These findings were validated by bioinformatic analyses demonstrating in various human cancers a negative correlation between the expression of RKIP and the expression of the EMT gene products. These findings suggest that targeting RKIP induction in cancer cells will result in multiple hits by inhibiting tumor growth, metastasis and reversal of chemo-immuno resistance. ABSTRACT: The Raf Kinase Inhibitor Protein (RKIP) is a unique gene product that directly inhibits the Raf/Mek/Erk and NF-kB pathways in cancer cells and resulting in the inhibition of cell proliferation, viability, EMT, and metastasis. Additionally, RKIP is involved in the regulation of cancer cell resistance to both chemotherapy and immunotherapy. The low expression of RKIP expression in many cancer types is responsible, in part, for the pathogenesis of cancer and its multiple properties. The inhibition of EMT and metastasis by RKIP led to its classification as a tumor suppressor. However, the mechanism by which RKIP mediates its inhibitory effects on EMT and metastases was not clear. We have proposed that one mechanism involves the negative regulation by RKIP of the expression of various gene products that mediate the mesenchymal phenotype as well as the positive regulation of gene products that mediate the epithelial phenotype via signaling cross talks between RKIP and each gene product. We examined several EMT mesenchymal gene products such as Snail, vimentin, N-cadherin, laminin and EPCAM and epithelial gene products such as E-cadherin and laminin. We have found that indeed these negative and positive correlations were detected in the signaling cross-talks. In addition, we have also examined bioinformatic data sets on different human cancers and the findings corroborated, in large part, the findings observed in the signaling cross-talks with few exceptions in some cancer types. The overall findings support the underlying mechanism by which the tumor suppressor RKIP regulates the expression of gene products involved in EMT and metastasis. Hence, the development of agent that can selectively induce RKIP expression in cancers with low expressions should result in the activation of the pleiotropic anti-cancer activities of RKIP and resulting in multiple effects including inhibition of tumor cell proliferation, EMT, metastasis and sensitization of resistant tumor cells to respond to both chemotherapeutics and immunotherapeutics.