Abstract
Simple SummaryThe human body consists of tissues and organs formed by cells. In each cell there is a switch that allows the cell to divide or not. In contrast, cancer cells have their switch on which allow them to divide and invade other sites leading to death. Over two decades ago, Doctor Kam Yeung, University of Toledo, Ohio, has identified a factor (RKIP) that is responsible for the on/off switch which functions normally in healthy tissues but is inactive or absent in cancers. Since this early discovery, many additional properties have been ascribed to RKIP including its role in inhibiting cancer metastasis and resistance to therapeutics and its role in modulating the normal immune response. This review describes all of the above functions of RKIP and suggesting therapeutics to induce RKIP in cancers to inhibit their growth and metastases as well as inhibit its activity to treat non-cancerous inflammatory diseases.Several gene products play pivotal roles in the induction of inflammation and the progression of cancer. The Raf kinase inhibitory protein (RKIP) is a cytosolic protein that exerts pleiotropic activities in such conditions, and thus regulates oncogenesis and immune-mediated diseases through its deregulation. Herein, we review the general properties of RKIP, including its: (i) molecular structure; (ii) involvement in various cell signaling pathways (i.e., inhibition of the Raf/MEK/ERK pathway; the NF-kB pathway; GRK-2 or the STAT-3 pathway; as well as regulation of the GSK3Beta signaling; and the spindle checkpoints); (iii) regulation of RKIP expression; (iv) expression’s effects on oncogenesis; (v) role in the regulation of the immune system to diseases (i.e., RKIP regulation of T cell functions; the secretion of cytokines and immune mediators, apoptosis, immune check point inhibitors and RKIP involvement in inflammatory diseases); and (vi) bioinformatic analysis between normal and malignant tissues, as well as across various immune-related cells. Overall, the regulation of RKIP in different cancers and inflammatory diseases suggest that it can be used as a potential therapeutic target in the treatment of these diseases.
Highlights
The Raf-1 kinase inhibitory protein (RKIP), referred to as PEBP-1 or PBP, is a member of the phosphatidylethanolamine-binding protein (PEBP) family that was originally isolated from the bovine brain [1]
STAT3 is a member of the signal transducer and activator of transcription (STAT) family, which is found in the cytoplasm, and upon being activated by phosphorylation, it translocates in the nucleus acting as a transcription factor for genes involved in the process of apoptosis, cell growth, survival, and differentiation [1,67]
These findings suggest that long noncoding RNAs (lncRNAs) x-inactive specific transcript (XIST) regulates RKIP expression in a competing endogenous RNA (ceRNA) manner and miR-23a plays a main role in XIST-mediated regulatory pathways
Summary
The Raf-1 kinase inhibitory protein (RKIP), referred to as PEBP-1 or PBP, is a member of the phosphatidylethanolamine-binding protein (PEBP) family that was originally isolated from the bovine brain [1]. It is a small, cytosolic protein [2] with wide expression in the tissues of various mammalian species, including monkeys, rats, chickens, and humans [1,3–7]. The binding of RKIP to both Raf-1 and MEK inhibits their phosphorylation and activation, leading to downstream suppression of the Raf-1-induced signaling and activity of AP-1dependent transcription [13]. RKIP inhibits phosphorylation and activation of the transcriptional factor STAT3, suppresses the expression of NRF2-ARE containing genes, and enhances glycogen synthase kinase 3 beta (GSK3Beta)-dependent signaling [1,14–19]. We review the literature on the pleiotropic activities and functions of RKIP and include: (i) RKIP structure, (ii) RKIP functions on cell signaling, (iii) regulation of RKIP expression, (iv) RKIP expression and tumor growth and resistance, (v) RKIP–immune system cross-talks in cancer and inflammatory diseases, (vi) bioinformatic analyses of RKIP expression levels and immune cells, and (vii) RKIP expression in cancer and inflammatory diseases [20,21]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
