Figure 2: The NF-κB signaling and prostate cancer. (a) Domain structure of NF-κB family members and its direct modulators IκB and IKK. The last two NF-κB members p50 and p52 are derived from the C-terminal processing of p105 and p100, respectively. All NF-κB family members contain an N-terminal Rel-homology domain (RHD) that governs the DNA binding, protein dimerization, and interaction to IκB. The Rel subfamily, RelA, RelB, and c-Rel, also contain a C-terminal transcriptional activation domain (TAD) and the subunit RelB has an additional leucine zipper (LZ) domain at the N-terminus. The IκB family mainly consists of IκBα, IκBβ, IκBγ, IκBε, and BCL-3 proteins (p100 also operates as an IκB-like protein in the non-canonical pathway). The IκB proteins contain ankyrin-repeat motifs (ANK) in their C-terminal region that interact with the RHD of NF-κB proteins and then prevent their nuclear translocation and DNA binding. The IκB kinase (IKK) complex is primarily composed of the two catalytic subunits IKK1 (or IKKα) and IKK2 (or IKKβ) and the scaffolding protein NEMO (or IKKγ). IKK1 and IKK2 are structurally related and both contain an LZ domain and a helix-loop-helix region (HLH), with a C-terminal portion containing a NEMO binding domain (NBD). NEMO has an alpha helical region along with two coiled-coil (CC) regions and a putative zinc finger (ZF) domain. (b) The TNF-dependent NF-κB signaling pathway. The canonical pathway in normal cells is used as an example for the signaling through TNF receptor. The activated IKK complex phosphorylates IκB that is then degraded by the proteasome. Upon degradation of IκB, the subunits of NF-κB are released and the complex is free to migrate to the nucleus. The canonical NF-κB pathway in prostate tumor cells is often constitutively activated, potentially due to increased levels of specific receptors like TNF receptors (TNFRs), which dramatically increase IκB degradation and the translocation of NF-κB dimers to the nucleus to activate κB-responsive genes involved in the development and progression of the tumor. Additionally, undetermined tyrosine kinase subpathways lead to NIK activation, which induces constitutive IKK activity and then constitutive NF-κB activation in androgen receptor-negative prostate cancer cell lines.