cancers Review RKIP Pleiotropic Activities in Cancer and Inflammatory Diseases: Role in Immunity Roni Touboul 1 , Stavroula Baritaki 2 , Apostolos Zaravinos 3,4 and Benjamin Bonavida 1, *   Citation: Touboul, R.; Baritaki, S.; Zaravinos, A.; Bonavida, B. RKIP Pleiotropic Activities in Cancer and Inflammatory Diseases: Role in Immunity. Cancers 2021, 13, 6247. https://doi.org/10.3390/ cancers13246247 Academic Editor: Alberto Maria Martelli Received: 2 November 2021 Accepted: 6 December 2021 Published: 13 December 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA 90095, USA; rtouboul@g.ucla.edu 2 Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, Heraklion, 71003 Crete, Greece; baritaks@uoc.gr 3 Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia 2404, Cyprus; a.zaravinos@euc.ac.cy 4 Basic and Translational Cancer Research Center (BTCRC), Cancer Genetics, Genomics and Systems Biology Laboratory, Nicosia 1516, Cyprus * Correspondence: bbonavida@mednet.ucla.edu; Tel.: +310-825-2233 Simple Summary: The 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. Abstract: Several gene products play pivotal roles in the induction of inflammation and the progres- sion 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. Keywords: RKIP; T cells; cancer; immunosuppression; immunotherapy; autoimmunity 1. Introduction The Raf-1 kinase inhibitory protein (RKIP), also referred to as PEBP-1 or PBP, is a member of the phosphatidylethanolamine-binding protein (PEBP) family that was orig- inally 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]. RKIP, as a very dynamic protein with a flexible pocket loop, exists in a number of states to enhance its functional switch [8,9]. The RKIP molecule appears to Cancers 2021, 13, 6247. https://doi.org/10.3390/cancers13246247 https://www.mdpi.com/journal/cancers