The RKIP and STAT3 Axis in Cancer Chemotherapy: Opposites Attract

Abstract

The acquisition of resistance to conventional therapies such as radiation and chemotherapeutic drugs remains a major obstacle in the successful treatment of cancer patients [1, 2]. In this regard, one of the major determinants of apoptosis sensitivity in cancer cells is the transcription factor nuclear factor kappa B (NFκB). Constitutive expression of NF-κB has been implicated in decreasing apoptosis in cancer cell lines [3]. NF-κB is an inducible transcription factor required for the upregulation of a large number of genes in response to inflammation, viral and bacterial infection, cell survival, cell adhesion, inflammation, differentiation, growth, and stress stimuli [4, 5]. Genes that are responsive to NF-κB activation include a variety of cytokines, cell adhesion molecules, acute phase response proteins, and apoptotic and anti-apoptotic proteins. It is believed that this reprogramming of gene expression is essential for cell survival during physiologic crisis situations. Active NF-κB is a dimer comprised of various members of the Rel family of proteins, and some form of NF-κB is expressed in most cell types. In unstimulated cells NF-κB is retained in the cytoplasm in an inactive form bound to a family of inhibitory proteins known as IκB (inhibitor of κB). Activation of NF-κB requires the phosphorylation and degradation of I-κB, which allows the NF-κB dimer to translocate to the nucleus [6, 7]. NF-κB can be activated by several signaling cascades and is subject to multiple levels of regulation. Considerable progress has been made in the identification of kinases that phosphorylate IκB and target it for subsequent degradation. In addition to its critical role in re-programming gene expression in response to infection and other stresses, NF-κB also mediates cell survival signals, protecting cells from apoptosis [8–10]. For example, cells derived from NF-κB p65 knockout mice are significantly more sensitive to TNFαinduced cytotoxicity than normal cells. Specificity to NF-κB was demonstrated by transfecting p65 into the knockout cells that reversed the cytotoxicity [11, 12]. Similar effects were also observed when NF-κB activation was ablated with an IκB dominantnegative mutant. Cells with compromised NF-κB activation are also more vulnerable to other proapoptotic signals such as ionizing radiation and cancer chemotherapeutic agents [13]. NF-κB has also been implicated in downregulating apoptosis in cncer cell lines that constitutively express elevated NF-κB activity by the observation that ablation of NF-κB activity by a variety of means induced apoptosis [3]. Many of the target genes that are activated by NF-κB are critical to the