title: Inhibition of Epithelial-to-Mesenchymal Transition (EMT) in Cancer by Nitric Oxide: Pivotal Roles of Nitrosylation of NF-κB, YY1 and Snail.
abstract: Treatment of cancer cell lines with high levels of nitric oxide (NO) via NO donors, such as DETANONOate, inhibits cell growth and survival pathways and sensitizes resistant tumor cells to apoptosis by chemoimmunotherapeutic drugs. In addition, we recently have reported that NO also inhibits the epithelial-to-mesenchymal transition (EMT) phenotype in metastatic cancer cell lines via dysregulation of the nuclear factor (NF)-κB/Snail/Yin Yang 1 (YY1)/Raf kinase inhibitor protein circuitry. The mechanism underlying NO-mediated dysregulation of this circuit was investigated, namely, NO-mediated inhibition of the activity of the transcription factors NF-κB, Snail, and YY1. We hypothesized that one mechanism of NO-mediated inhibition may invoke the NO-induced S-nitrosylation of these transcription factors. We demonstrate in metastatic and EMT+human prostate carcinoma cell lines that treatment with NO results in the S-nitrosylation of NF-κB (p50), Snail, and YY1 and inhibits their activities, resulting in the reversal of the EMT phenotype into a mesenchymal-to-epithelial transition phenotype. These findings suggest that NO donors may be potential therapeutic agents in both the reversal of resistance and the inhibition of EMT and metastasis.
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bonavida
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Baritaki
keywords: Raf kinase inhibitor protein; Yin Yang 1; epithelial-to-mesenchymal transition (EMT); metastasis; nitric oxide
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