Double trouble: cytosolic and nuclear IKKα in cancer

Abstract

IκB kinase alpha (IKKα) is a serine/threonine kinase originally known for its role in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling, which integrates inflammatory processes and cancer. IKKα can function within the IKK complex in canonical NF-κB signalling, alongside its homologous family member, IKKβ, and regulatory subunit IKKγ (NEMO). However, a key role for IKKα is its ability to promote non-canonical NF-κB signalling. Additionally, the dynamic ability of IKKα to shuttle between the cytosol and nucleus, mediates NF-κB-independent effects which further its role in inflammation and tumour progression. More recently, an endosomal-generated, nuclear-active IKKα isoform, p45-IKKα has been discovered and implicated in cancer and chemoresistance. This review focuses on current knowledge of the complex and intricate roles of nuclear and cytosolic IKKα in promoting tumour progression. By highlighting the molecular roles of IKKα in several cancer subtypes, and its integral roles in many of the hallmarks of cancer throughout this review, we highlight the therapeutic potential of IKKα as a future anti-cancer drug target.

Keywords: IKKα; NF-κB; cancer; cytosolic; nuclear.

Figure 1.

A diagrammatical representation of the canonical and non-canonical NF-κB signalling pathways. Canonical NF-κB signalling is stimulated by a plethora of inflammatory cues, while non-canonical NF-κB signalling is activated by specific TNF-superfamily members. Canonical NF-κB signalling relies on activation of the IKK complex, consisting of IKKα, IKKβ and IKKγ. IKKβ phosphorylation induces phosphorylation and degradation of IκBα, and downstream nuclear translocation of p50-p65 NF-κB heterodimers. IKKα phosphorylation results in rapid phosphorylation of p100, another NF-κB family member, but the subsequent downstream events remain unexplored. Non-canonical NF-κB signalling is dependent on IKKα homodimers, leading to phosphorylation of p100, resulting in its proteasomal degradation into p52. This facilitates the formation of p52-RelB heterodimers, which translocate to the nucleus. Both signalling pathways promote distinct subsets of pro-inflammatory and oncogenic genes. Original figure created on BioRender.com.

Figure 2.

Structural representation of the IKK family member subunits. (A) The structure of IKKα comprised kinase domain with two phosphorylation sites, Ser176 and Ser180, as well as a scaffold dimerization domain and a C-terminal NEMO-binding domain, which facilitates IKKα–IKKγ binding. (B) The structure of an endosomal-derived, nuclear active IKKα isoform, p45-IKKα. This truncated form has been shown to be phosphorylated at one site by TAK1, Ser180 and lacks the other regulatory domains which IKKα possesses. (C) IKKβ possesses a closely related structure to IKKα, containing a kinase domain with two phosphorylation residues, Ser177 and Ser181, responsible for its action, a scaffold dimerization domain and a NEMO-binding domain. IKKβ also contains an additional ubiquitin-like domain. (D) IKKγ contains a coiled coil 1 domain involved in IKKα/IKKβ activation when bound, linker 1 which is a Tax/v-FLIP domain and LPS/cytokine domain consisting of coiled coil 2, ubiquitin binding domain, leucine zipper, linker 2 and another ubiquitin binding domain known as zinc finger. KD, kinase domain; ULD, ubiquitin-like domain; SDD, scaffold dimerization domain; NBD, NEMO-binding domain; CC1, coiled coil 1; L1, linker 1; CC2, coiled coil 2; NOA, ubiquitin binding domain; LZ, leucine zipper; L2, linker 2; ZF, zinc finger. Original figure created on BioRender.com.

Figure 3.

A summary diagram of the roles of IKKα in hallmarks of cancer. This figure depicts a summary of some examples of the mechanisms by which IKKα promotes cancer hallmarks, which in turn promotes tumour progression. Original figure created on BioRender.com.