Attribution of NF-κB Activity to CHUK/IKKα-Involved Carcinogenesis

Simple Summary CHUK/IKK alpha has emerged as a novel tumor suppressor in several organs of humans and mice. In general, activation of NF-kappa B promotes inflammation and tumorigenesis. IKK alpha reduction stimulates inflammatory responses including NF-kappa B's targets and NF-kappa B-independent pathways for tumor promotion. Specific phenomena from genetically-modified mice and human TCGA database show the crosstalk between IKK alpha and NF-kappa B although their nature paths for normal organ development and the disease and cancer pathogenesis remains largely under investigation. In this review, we focus on the interplay between IKK alpha and NF-kappa B signaling during carcinogenesis. A better understanding of their relationship will provide insight into therapeutic targets of cancer. 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-kappa B kinase alpha (IKK alpha), 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-kappa B kinase complex (IKK), which is composed of IKK alpha, IKK beta, and IKK gamma (NEMO). IKK phosphorylates serine residues 32 and 36 of I kappa B alpha, a nuclear factor-kappa B (NF-kappa B) inhibitor, to induce I kappa B alpha protein degradation, resulting in the nuclear translocation of NF-kappa B dimers that function as transcriptional factors to regulate immunity, infection, lymphoid organ/cell development, cell death/growth, and tumorigenesis. NF-kappa B 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-kappa B in carcinogenesis has been predominately accepted in the field. Surprisingly, IKK alpha has emerged as a novel suppressor for skin, lung, esophageal, and nasopharyngeal squamous cell carcinoma, as well as lung and pancreatic adenocarcinoma (ADC). Thus, Ikk alpha loss is a tumor driver in mice. On the other hand, lacking the RANKL/RANK/IKK alpha pathway impairs mammary gland development and attenuates oncogene- and chemical carcinogen-induced breast and prostate tumorigenesis and metastasis. In general, NF-kappa B activation leads one of the major inflammatory pathways and stimulates tumorigenesis. Since IKK alpha and NF-kappa B 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-kappa B to CHUK/IKK alpha-involved carcinogenesis.

Automated summary

CHUK/IKK alpha has emerged as a novel tumor suppressor in several human and mouse organs, with a strong association with NF-kappa B. However, the roles of IKK alpha and NF-kappa B in normal organ development, disease, and cancer pathogenesis require further investigation.