Abstract
RAF-kinase inhibitor protein (RKIP) is a well-established tumor suppressor that is frequently downregulated in a plethora of solid and hematological malignancies. RKIP exerts antimetastatic and pro-apoptotic properties in cancer cells, via modulation of signaling pathways and gene products involved in tumor survival and spread. Here we review the contribution of RKIP in the regulation of early metastatic steps such as epithelial–mesenchymal transition (EMT), migration, and invasion, as well as in tumor sensitivity to conventional therapeutics and immuno-mediated cytotoxicity. We further provide updated justification for targeting RKIP as a strategy to overcome tumor chemo/immuno-resistance and suppress metastasis, through the use of agents able to modulate RKIP expression in cancer cells.
Highlights
The RAF-kinase inhibitor protein [RKIP or Phosphatidylethanolamine-binding protein-1 (PEBP1)]has been critically involved in the regulation of distinct biological processes, through interactions with several signaling cascades, such as the mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), G protein-coupled receptors (GPCR) and glycogen synthase kinase3β (GSK3β) pathways [1,2,3,4,5,6,7]
Our analysis shows that RKIP exhibits its highest levels in adrenocortical carcinoma (ACC), liver hepatocellular carcinoma (LIHC), and thyroid carcinoma (THCA), and its lowest expression was detected in acute myeloid leukemia (LAML), esophageal carcinoma (ESCA), and stomach and esophageal carcinomas (STES) (Figure 1)
RKIP extends its indirect regulatory role downstream of HMGA2, in a number of additional let-7/HMGA2 targets involved in the metastatic process, as shown by gene and microRNA expression analyses performed in breast cancer cell lines [14]
Summary
The RAF-kinase inhibitor protein [RKIP or Phosphatidylethanolamine-binding protein-1 (PEBP1)]. The reduction or loss of RKIP expression has been associated with the initiation and progression of multiple diseases, including cancer. RKIP was shown to act as an endogenous onco-suppressing protein affecting negatively tumor cell survival, proliferation, and metastasis [8]. The most well-reported role of RKIP is in the metastasis suppression [9,10,11,12,13,14,15]. The main goal of this review is to update the vital impact of the RKIP expression levels in cancer cells on their sensitivity to cytotoxic therapies and on their metastatic potential. We mainly discuss the regulatory role of RKIP on multiple signaling modules reported so far to be involved in metastasis initiation and therapeutic resistance in various cancer types. We discuss the most recent advances on the prognostic and therapeutic applications of RKIP expression levels in cancer
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