RKIP-mediated chemo-immunosensitization of resistant cancer cells via disruption of the NF-κB/Snail/YY1/RKIP resistance-driver loop.

Cancer remains one of the most dreadful diseases. Whereas most treatment regimens for various cancers have resulted in improved clinical responses and sometimes cures, unfortunately, subsets of cancer patients are either pretreatment resistant or develop resistance following therapy. These subsets of patients develop cross-resistance to unrelated therapeutics and usually succumb to death. Thus, delineating the underlying molecular mechanisms of resistance of various cancers and identifying molecular targets for intervention are the current main focus of research investigations. One approach to investigate cancer resistance has been to identify pathways that regulate resistance and develop means to disrupt these pathways in order to override resistance and sensitize the resistant cells to cell death. Hence, we have identified one pathway that is dysregulated in cancer, namely, the NF-κB/Snail/YY1/RKIP loop, that has been shown to regulate, in large part, tumor cell resistance to apoptosis by chemotherapeutic and immunotherapeutic cytotoxic drugs. The dysregulated resistant loop is manifested by the overexpression of NF-κB, Snail, and YY1 activities and the underexpression of RKIP. The induction of RKIP expression results in the downregulation of NF-κB, Snail, and YY1 and the sensitization of resistant cells to drug-induced apoptosis. These findings identified RKIP, in addition to its antiproliferative and metastatic suppressor functions, as an anti-resistance factor. This brief review describes the role of RKIP in the regulation of drug sensitivity via disruption of the NF-κB/Snail/ YY1/RKIP loop that regulates resistance in cancer cells.