Double trouble : cytosolic and nuclear IKKα in cancer

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Tinto, Kirsty and Cunningham, Margaret and Plevin, Robin (2025) Double trouble : cytosolic and nuclear IKKα in cancer. Open Biology, 15 (8). 240375. ISSN 2046-2441 (https://doi.org/10.1098/rsob.240375)

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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.

ORCID iDs

Tinto, Kirsty ORCID logoORCID: https://orcid.org/0009-0008-7954-0742, Cunningham, Margaret ORCID logoORCID: https://orcid.org/0000-0001-6454-8671 and Plevin, Robin ORCID logoORCID: https://orcid.org/0000-0002-7849-1220;
CORE (COnnecting REpositories)