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Critical Reviews™ in Immunology
IF: 1.404 5-Year IF: 3.347 SJR: 0.706 SNIP: 0.55 CiteScore™: 2.19

ISSN Print: 1040-8401
ISSN Online: 2162-6472

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Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.v30.i1.20
pages 31-46

Viral Infection and Cancer: The NF-κB/Snail/RKIP Loop Regulates Target Cell Sensitivity to Apoptosis by Cytotoxic Lymphocytes

Stavroula Baritaki
Department of Microbiology and Molecular Genetics, David Geffen School of Medicine, Jonnson Comprehensive Cancer Center, University of California(UCLA), USA
Benjamin Bonavida
Department of Microbiology, Immunology, & Molecular Genetics, David Geffen School of Medicine, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747

ABSTRACT

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-α (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-κB (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-κB inhibitors. Inhibition of NF-κB 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-κB. Snail siRNA reverses resistance to TRAIL. Because RKIP negatively regulates NF-κB, we propose that the resistant cell phenotype could be maintained through Snail-mediated RKIP suppression which supports the constitutive NF-κB 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-κB-Snail-RKIP phenotype. Alternative therapeutic interventions, such as various inhibitors, NF-κB inhibitors, and siRNAs, are presented.


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