title: Mechanisms of nitric oxide-mediated inhibition of EMT in cancer: inhibition of the metastasis-inducer Snail and induction of the metastasis-suppressor RKIP.
abstract: The role of nitric oxide (NO) in cancer has been controversial and is based on the levels of NO and the responsiveness of the tumor type. It remains unclear whether NO can inhibit the epithelial to mesenchymal transition (EMT) in cancer cells. EMT induction is mediated, in part, by the constitutive activation of the metastasis-inducer transcription factor, Snail and EMT can be inhibited by the metastasis-suppressor Raf-1 kinase inhibitor protein (RKIP) and E-cadherin. Snail is transcriptionally regulated by NF-κB and in turn, Snail represses RKIP transcription. Hence, we hypothesized that high levels of NO, that inhibit NF-κB activity, may also inhibit Snail and induce RKIP and leading to inhibition of EMT. We show that treatment of human prostate metastatic cell lines with the NO donor, DETANONOate, inhibits EMT and reverses both the mesenchymal phenotype and the cell invasive properties. Further, treatment with DETANONOate inhibits Snail expression and DNA-binding activity in parallel with the upregulation of RKIP and E-cadherin protein levels. The pivotal roles of Snail inhibition and RKIP induction in DETANONOate-mediated inhibition of EMT were corroborated by both Snail silencing by siRNA and by ectopic expression of RKIP. The in vitro findings were validated in vivo in mice bearing PC-3 xenografts and treated with DETANONOate. The present findings show, for the first time, the novel role of high subtoxic concentrations of NO in the inhibition of EMT. Thus, NO donors may exert therapeutic activities in the reversal of EMT and metastasis.
authors.affiliation: Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Baritaki
authors.forename: Sara
authors.initials: S
authors.lastname: Huerta-Yepez
authors.forename: Anna
authors.initials: A
authors.lastname: Sahakyan
authors.forename: Iordanis
authors.initials: I
authors.lastname: Karagiannides
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Bakirtzi
authors.forename: Ali
authors.initials: A
authors.lastname: Jazirehi
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bonavida
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology; D010641:Phenotype; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide