Viral infection and cancer: the NF-kappaB/Snail/RKIP loop regulates target cell sensitivity to apoptosis by cytotoxic lymphocytes.

The anti-viral/tumor cytotoxic T cells exert their killing mechanisms by the granzyme-perforin and death ligand-induced necrosis and apoptosis. These death ligands include TNF-alpha (tumor-necrosis factor-alpha), FasL (Fas ligand), and TRAIL (TNF-related apoptosis-inducing ligand). However, many target cells resist killing by the cytotoxic T cells. Tis review discusses potential novel underlying mechanisms of resistance and implicate an NF-kappaB (nuclear factor kappa beta)-Snail (SNAI-1)-RKIP (Raf-1 kinase inhibitor protein) circuitry in resistant targets. TRAIL-mediated killing of a tumor cell line is used as an example to illustrate the circuitry. Tumor cells resistant to TRAIL-mediated apoptosis can be sensitized by NF-kappaB inhibitors. Inhibition of NF-kappaB results in the induction of RKIP. RKIP overexpression sensitizes the cells to TRAIL. RKIP is induced following inhibition of the RKIP transcription repressor, Snail, downstream of NF-kappaB. Snail siRNA reverses resistance to TRAIL. Because RKIP negatively regulates NF-kappaB, we propose that the resistant cell phenotype could be maintained through Snail-mediated RKIP suppression which supports the constitutive NF-kappaB activation. This review introduces a new paradigm, namely, that the cytotoxic T-cell response to viral infection and/or cancer may be compromised by the target cells expressing the resistant NF-kappaB-Snail-RKIP phenotype. Alternative therapeutic interventions, such as various inhibitors, NF-kappaB inhibitors, and siRNAs, are presented.