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

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.

Studies of Erk1/2 with Respect to Tumor Aggressiveness in B16f10 Murine Melanoma Cells

“…The levels of expression and activity of RKIP suggested that specific inhibition of ERK elevates the expression and activity of RKIP, which again suggests a possible feedback mechanism. This is in parallel to many recent evidences, which shows RKIP as a negative regulator of ERK (Cessna et al, 2022;Tang et al, 2010) .Specific inhibition of ERK by siRNA does not alter the expression and activity of MEK1/2 showing that targeted ERK modulation may result in better treatment of melanoma. The decreased levels of cFOS indicated that transcription regulation downstream of ERK might be through cFOS.…”

A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity

“…We observed the team strength of the wild-type (WT) network to be much greater than that of all 1000 randomly generated networks (figure 3 d ). This observation suggests that the organization of these molecular players into ‘teams’ in this network is not a coincidence, but rather a unique topological signature that can possibly facilitate specific couplings between cellular behaviour, such as the association of EMT with stemness and tamoxifen resistance [50,51] and opposite roles of RKIP and BACH1 in EMT [46,52].…”

Roles of hypoxia-inducible factor in hepatocellular carcinoma under local ablation therapies

“…As known, E-cadherin, N-cadherin, vimentin, and Snail are the markers of EMT ( Cessna et al, 2022 ). Tong et al (2017) mimicked the IRFA through thermal treatment under hypoxic conditions and found that the protein levels of HIF-1α, N-cadherin, vimentin, Snail, and TGF-β1 following IRFA were significantly elevated, while the expression of E-cadherin was reduced in HCC cells.…”