Nitric Oxide Inhibits Tumor Cell Metastasis via Dysregulation of the NF-κB/Snail/RKIP Loop

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The major cause of cancer-related death is metastasis. A clearer understanding of the underlying mechanisms of metastasis should improve current therapies following the design of new treatment modalities. In this chapter, we discuss the therapeutic potential of endogenous nitric oxide (NO) or NO donors in the inhibition of both the tumor progression and the induction of metastasis through inhibition of the epithelial to mesenchymal transition (EMT). Briefly, the findings show that NO donors’ treatment of metastatic human cancer cell lines results in several modifications of cell survival signaling pathways that regulate metastasis and particularly EMT. NO donors inhibit NF-κB activity and downstream the metastasis inducer transcription factor, Snail. In addition, NO donors trigger the metastasis suppressor Raf-1 kinase inhibitor protein (RKIP) via inhibition of the RKIP transcription repressor Snail. NO-induced inhibition of NF-κB and Snail and induction of RKIP established the NO-induced dysregulation of the NF-κB/Snail/RKIP circuitry in the regulation of metastasis. These findings suggest the therapeutic role of NO donors in the inhibition of metastasis.