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.
Baritaki
Stavroula
S
Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
Bonavida
Benjamin
B
D017209:Apoptosis / Q000276:immunology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology*; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism*; D014777:Virus Diseases / Q000276:immunology*
D016328:NF-kappa B; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors