Roles Each of Snail, Yin Yang 1, and RKIP in the Regulation of Tumor Cells Chemo- Immuno-Resistance to Apoptosis

The current anti-cancer therapeutic armamentarium consists of surgery, chemotherapy, radiation, hormonal therapy, immunotherapy, and combinations thereof. Initial treatments usually result in objective clinical responses with prolongation of overall survival (OS) and progression-free survival (PFS) in a large subset of the treated patients. However, at the onset, there is a subset of patients who does not respond and another subset that initially responded but experiences relapses and recurrences. These latter subsets of patients develop a state of cross-resistance to a variety of unrelated therapies. Therefore, there is an urgent need to first unravel the underlying mechanisms of resistance and associated gene products that regulate the cross-resistance. Such gene products are potential therapeutic targets as well as potential prognostic/diagnostic biomarkers. In this context, we have identified three interrelated gene products involved in resistance, namely, Snail, YY1, and RKIP that are components of the dysregulated NF-κB/Snail/YY1/RKIP loop in many cancers. In this review, we will discuss the roles each of Snail, YY1 and RKIP in the regulation of tumor cell resistance to chemo and immunotherapies. Since these same gene products have also been shown to be involved in the regulation of the EMT phenotype and metastasis, we suggest that targeting any of these three gene products can simultaneously inhibit tumor cell resistance and metastasis.