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Forum on Immunopathological Diseases and Therapeutics
SJR: 0.309 SNIP: 0.041 CiteScore™: 0.18

ISSN Печать: 2151-8017
ISSN Онлайн: 2151-8025

Archives: Volume 1, 2010 to Volume 7, 2016

Forum on Immunopathological Diseases and Therapeutics

DOI: 10.1615/ForumImmunDisTher.v1.i3.40
pages 219-230

Inhibition of Snail-induced Epithelial-Mesenchymal Transition and Induction of the Tumor Metastasis Suppressor Gene Raf-1 Kinase Inhibitor Protein (RKIP) by DETANONOate

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

Краткое описание

Tumor metastasis initiates through the epithelial to mesenchymal transition (EMT) process. Unraveling the underlying molecular mechanisms of EMT should identify novel targets for therapeutic intervention. Nitric oxide (NO) sensitizes resistant tumors to apoptosis through inhibition of the constitutively activated nuclear factor (NF)-κB signaling. Since NF-κB hyperactivation is associated with tumor metastasis via regulation of EMT, we hypothesized that NF-κB inhibition by NO should suppress EMT. We demonstrate that treatment of the metastatic human prostate cancer cell lines DU145 and PC-3 with (Z)-l-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-l-ium-l,2-diolate (DETANONOate) inhibits significantly the constitutive NF-κB activity through p50 S-nitrosylation and the expression of the mesenchymal markers vimentin and fibronectin, where it augments the expression of the epithelial markers E-cad-herin and cytokeratin 18. Also, the NO-treated cells had decreased migratory and invasive properties. We further show that NO-mediated NF-κB inhibition results in downstream inhibition of its transcriptional target, Snail (SNAI1), a known EMT inducer. Snail inhibition, in turn, triggers the induction of the metastasis suppressor gene products Raf-1 kinase inhibitor protein (RKIP) and E-cadherin, whose transcriptions are negatively regulated by Snail. Thus, RKIP induction further suppresses NF-κB and consequently inhibits EMT. The above findings were corroborated by cell transfections with Snail siRNA and RKIP overexpression vectors and were validated in vivo in mice bearing PC-3 xenografts that were treated with DETANONOate. These findings establish for the first time the role of NO in the inhibition of EMT via dysregulation of the NF-κB-Snail-RKIP circuitry, and suggest the potential therapeutic application of NO donors in the regulation of metastasis.

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