Effects of NF-κB manipulation on cancer-associated bone disease

Introduction

The NF-κB signal transduction pathway plays a major role in inflammation and immunity, among many physiological activities and processes [ ]. The activation of NF-κB signaling predominantly occurs through two pathways: the canonical (classical) or noncanonical (alternative) pathway [ , ] ( Fig. 19.1 ). A plethora of pro- and non-inflammatory stimuli are known to activate these pathways via binding to their respective receptors, a process that triggers the recruitment of various adaptor proteins, phosphorylation of cytoplasmic signaling proteins, and activation of five structurally related members, namely RelA (p65), RelB, c-Rel, NF-κB1 (p105), and NF-κB2 (p100), that share a highly conserved Rel homology domain [ , , ]. In turn, the Rel domain binds to promoter and enhancer sites of various genes involved in a variety of processes that include cell differentiation, proliferation, fusion, survival, and death [ , ].

The canonical NF-κB pathway is predominately activated through B cell receptors (BCRs) or tumor necrosis factor receptors (TNFRs) and involves adaptor proteins from the TNF receptor–associated factor (TRAF) and receptor interacting protein (RIP) families [ , ]. TRAF1 to TRAF7 are adaptor proteins implicated in many physiological and pathophysiological activities including inflammation, immunity, cancer, and bone remodeling [ , ]. TRAFs function downstream of multiple receptors for proinflammatory factors including RANKL, IL-1β, and TNF-α [ ] and, particularly, TRAF2, TRAF5, and TRAF6 are essential for the regulation of bone remodeling [ ]. TRAF6/NF-κB signaling is initiated by the interaction of ligands, such as cluster of differentiation 40 (CD40) ligand (CD40L) or RANKL, with their respective receptors [ ]. This initiates the recruitment of TRAF6 to the membrane, followed by the binding of various adaptor proteins, such as TAK1 protein from the IKK family, to form a complex [ ]. This in turn leads to the phosphorylation and subsequent ubiquitination and degradation of IκB-α, liberating p50/p65 to translocate to the nucleus, where it binds to DNA and activates the release of various proinflammatory mediators [ ]. In contrast, the noncanonical NF-κB pathway involves the recruitment and binding of NF-κB-inducing kinase (NIK) and adaptor proteins such as TRAF2 and TRAF3 that activate IKKα, leading to the phosphorylation of p100-RelB complex that in turn releases the p52-RelB complex [ , ] ( Fig. 19.1 ).

Constitutive and induced activation of both canonical and noncanonical NF-κB pathways have been linked to the initiation and progression of metastasis [ , ] and the development of resistance to chemotherapy [ , , ]. The skeleton is considered an ideal environment for metastatic cancer cells expressing high levels of components of the NF-κB pathway due to its richness in NF-κB-activating factors and cytokines [ , ]. In bone, osteotropic cancer cells secrete NF-κB-activating mediators that directly or indirectly disrupt the balance of the bone remodeling process by interfering with the differentiation and activity of a heterogeneous population of bone cells, particularly osteoclasts and osteoblasts [ , ]. Furthermore, cancer cells express receptors for various bone-derived factors such as TGF-β and osteolytic factor receptor activator for NF-κB (RANKL), and systemic mediators including the proinflammatory cytokine TNF-α and hormone PTH-related protein (PTHrP) [ , , ]. This deregulation of normal bone remodeling by cancer cells results in what is known as the “vicious cycle” ( Fig. 19.2 ), a process characterized by excessive osteolytic bone resorption, enhanced osteoblastic differentiation, and osteoclastogenesis, or both [ ]. In addition to acting directly in osteoclasts and osteoblasts, tumor-derived proinflammatory mediators and growth factors have also been shown to stimulate the production of osteolytic factors such as RANKL, IL-1β, and TNF-α by immune cells [ ].

The forthcoming sections review studies that have shown evidence to support the hypothesis that genetic and pharmacological inhibition of NF-κB can be of value in the treatment of bone disease associated with various cancers that originate in bone and distant organs including prostate, breast, and skin.

Role of NF-κB on bone metastasis