Abstract
Studies analyzing human cancer genome sequences and genetically modified mouse models have extensively expanded our understanding of human tumorigenesis, even challenging or reversing the dogma of certain genes as originally characterized by in vitro studies. Inhibitor-κB kinase α (IKKα), which is encoded by the conserved helix-loop-helix ubiquitous kinase (CHUK) gene, is first identified as a serine/threonine protein kinase in the inhibitor-κB kinase complex (IKK), which is composed of IKKα, IKKβ, and IKKγ (NEMO). IKK phosphorylates serine residues 32 and 36 of IκBα, a nuclear factor-κB (NF-κB) inhibitor, to induce IκBα protein degradation, resulting in the nuclear translocation of NF-κB dimers that function as transcriptional factors to regulate immunity, infection, lymphoid organ/cell development, cell death/growth, and tumorigenesis. NF-κB and IKK are broadly and differentially expressed in the cells of our body. For a long time, the idea that the IKK complex acts as a direct upstream activator of NF-κB in carcinogenesis has been predominately accepted in the field. Surprisingly, IKKα has emerged as a novel suppressor for skin, lung, esophageal, and nasopharyngeal squamous cell carcinoma, as well as lung and pancreatic adenocarcinoma (ADC). Thus, Ikkα loss is a tumor driver in mice. On the other hand, lacking the RANKL/RANK/IKKα pathway impairs mammary gland development and attenuates oncogene- and chemical carcinogen-induced breast and prostate tumorigenesis and metastasis. In general, NF-κB activation leads one of the major inflammatory pathways and stimulates tumorigenesis. Since IKKα and NF-κB play significant roles in human health, revealing the interplay between them greatly benefits the diagnosis, treatment, and prevention of human cancer. In this review, we discuss the intriguing attribution of NF-κB to CHUK/IKKα-involved carcinogenesis.
Highlights
Five nuclear factor-κB (NF-κB) transcriptional factors, including RelA (p65), RelB, c-Rel, NF-κB1 (p50), and NF-κB2 (p52), are differentially expressed in a wide range of cell types and execute their physiological functions through the compositions of their homodimers or heterodimers (Figure 1) [1]
These analyses indicate that IKKα loss and reduction elevate the expression of NF-κB targets, such as TNFα and IL-1, which are correlated with skin inflammation and tumorigenesis
P52 reduction inhibits lung tumorigenesis in the same setting [73]. These results suggest that NF-κB contributes to lung ADC development and that, during tumorigenesis, IKKα and NF-κB may function in two parallel pathways
Summary
Five NF-κB transcriptional factors, including RelA (p65), RelB, c-Rel, NF-κB1 (p50), and NF-κB2 (p52), are differentially expressed in a wide range of cell types and execute their physiological functions through the compositions of their homodimers or heterodimers (Figure 1) [1]. IKK stimulates canonical and non-canonical NF-κB activation and transduces signals from These IKK subunits mice display severe are not functionally redundant phenotypes3(oTfa1b4le 1), . IKKα loss, promotes the development of cutaneous, lung, and esophageal squamous cell carcinomas (SCCs) and lung and pancreatic ADCs [19,22,23,35,36,37,38,39,40], which are associated with increased NF-κB related targets and inflammation. The basal cells of the squamous epithelium express keratin 5 (K5), K14, and p63 and are able to proliferate and differentiate in response to various stimuli, including growth factors, cytokines, chemokines, inflammatory irritants, and chemical carcinogens. Deletions and reduction of CHUK, which encodes IKKα, reportedly promote SCC development in the skin, lungs, oral cavity, esophagus, and nasopharynx of humans [19,22,23,35,36,37,38,39,40]
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