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Critical Reviews™ in Immunology
インパクトファクター: 1.352 5年インパクトファクター: 3.347 SJR: 1.022 SNIP: 0.55 CiteScore™: 2.19

ISSN 印刷: 1040-8401
ISSN オンライン: 2162-6472

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Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.v29.i3.40
pages 241-254

The Activated NF-κB-Snail-RKIP Circuitry in Cancer Regulates Both the Metastatic Cascade and Resistance to Apoptosis by Cytotoxic Drugs

Katherine Wu
Department of Microbiology, Immunology & Molecular Genetics, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-736422
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

要約

Premalignant cells acquire a series of genetic and epigenetic changes that are responsible for cell proliferation in the absence of growth factors. It is not yet defined how the initial steps of the invasive metastatic cascade are acquired. New insights into the initial steps of the metastatic process were revealed by a set of regulators that induced the differentiation program termed "the epithelial to mesenchymal transition (EMT)." EMT is regulated by distinct transcription factors such as Snail, Slug and TWIST. Overexpression of Snail in cancer is responsible, in part, for the induction of EMT through the downregulation of E-cadherin and cytokeratins and the induction of mesenchymal protein expression such as vimentin, fibronectin, N-cadherin, metalloproteases, and invasiveness. In contrast, the metastatic suppressor Raf-kinase inhibitor protein (RKIP) is poorly expressed in primary cancers and absent in various metastatic cancers. RKIP inhibits NF-κB activity through direct interaction with NIK and TAK1. Snail was shown to suppress RKIP transcription and expression, and Snail is transcriptionally regulated by NF-κB. Thus, a circuitry is developed in which overexpression of Snail in tumors inhibits RKIP and induces EMT. In addition, NF-κB, Snail, and RKIP have been shown to regulate tumor-cell resistance to apoptotic stimuli. Inhibition of NF-κB and Snail and induction of RKIP sensitize resistant tumor cells to apoptosis by various chemotherapeutic and immunotherapeutic drugs. Furthermore, the ratio of Snail over RKIP expression in tumor cells is of prognostic significance and predicts response to cytotoxic therapies. Thus, pharmacological agents regulating the RKIP-NF-κB-Snail loop can be used as both sensitizing agents for apoptosis when combined with cytotoxic therapies as well as inhibitors of metastasis.


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