RKIP in human diseases and its potential as a prognostic indicator and therapeutic target

Abstract

The Raf kinase inhibitory protein (RKIP) is an inhibitor of the RAF/MEK/ERK and NF-κB signaling pathways, through which it regulates several key processes of the cell's physiology, such as its proliferation, motility and apoptosis. RKIP is also recognized as a suppressor of metastasis and a chemo-immuno sensitizing gene product. Therefore, its role is critical in different human diseases, and particularly, cancer. Prognosis is also associated with the status of RKIP, since its downregulation across distinct cancer types contributes to tumor progression and metastasis, and on the other hand, its overexpression results in the inhibition of tumor survival, proliferation, metastasis, and resistance. Here, we show that RKIP expression correlates negatively with overall and disease-free survival of patients across different cancer types, including skin melanoma, pancreatic, kidney, and lung cancers, corroborating its potential as an independent prognostic factor. Furthermore, RKIP is a favorable therapeutic target in a variety of cancers. Novel treatment strategies that incorporate conventional drugs in combination with new agents that promote RKIP expression show alleviation of cancer aggressiveness and can resensitize resistant tumors toward chemotherapy and immune-mediated cytotoxicity.