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

Abstract

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-kappaB activity through direct interaction with NIK and TAK1. Snail was shown to suppress RKIP transcription and expression, and Snail is transcriptionally regulated by NF-kappaB. Thus, a circuitry is developed in which overexpression of Snail in tumors inhibits RKIP and induces EMT. In addition, NF-kappaB, Snail, and RKIP have been shown to regulate tumor-cell resistance to apoptotic stimuli. Inhibition of NF-kappaB 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-kappaB-Snail loop can be used as both sensitizing agents for apoptosis when combined with cytotoxic therapies as well as inhibitors of metastasis.