Library Subscription: Guest
Begell Digital Portal Begell Digital Library eBooks Journals References & Proceedings Research Collections
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

Volume 40, 2020 Volume 39, 2019 Volume 38, 2018 Volume 37, 2017 Volume 36, 2016 Volume 35, 2015 Volume 34, 2014 Volume 33, 2013 Volume 32, 2012 Volume 31, 2011 Volume 30, 2010 Volume 29, 2009 Volume 28, 2008 Volume 27, 2007 Volume 26, 2006 Volume 25, 2005 Volume 24, 2004 Volume 23, 2003 Volume 22, 2002 Volume 21, 2001 Volume 20, 2000 Volume 19, 1999 Volume 18, 1998 Volume 17, 1997 Volume 16, 1996 Volume 15, 1995 Volume 14, 1994

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


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.

Articles with similar content:

Dual Roles of Raf-1 Kinase Inhibitor Protein in the Regulation of Both Tumor Cell Resistance to Apoptotic Stimuli and Epithelial to Mesenchymal Transition
Forum on Immunopathological Diseases and Therapeutics, Vol.2, 2011, issue 1
Stavroula Baritaki, Kam C. Yeung, Benjamin Bonavida
Molecular Parameters of Head and Neck Cancer Metastasis
Critical Reviews™ in Eukaryotic Gene Expression, Vol.21, 2011, issue 2
Sanjay L. Bhave, Theodoras N. Teknos, Quintin Pan
Role of NF-κB in Tumorigenesis
Forum on Immunopathological Diseases and Therapeutics, Vol.4, 2013, issue 2
Gautam Sethi, Muthu K. Shanmugam, Alan P. Kumar, Benny K. H. Tan
RKIP-Mediated Chemo-Immunosensitization of Resistant Cancer Cells via Disruption of the NF-κB/Snail/YY1/RKIP Resistance-Driver Loop
Critical Reviews™ in Oncogenesis, Vol.19, 2014, issue 6
Benjamin Bonavida
The Activated NF-κB-Snail-RKIP Circuitry in Cancer Regulates Both the Metastatic Cascade and Resistance to Apoptosis by Cytotoxic Drugs
Critical Reviews™ in Immunology, Vol.29, 2009, issue 3
Katherine Wu, Benjamin Bonavida