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| Tumorigenesis: IKKα goes nuclear
A new nuclear role has been described for IκB kinase alpha (IKKα) in the promotion of metastasis in response to proinflammatory signals. Nuclear factor kappa B (NF-κB) and its associated regulatory proteins (inhibitor of NF-κB (IκB) and IκB kinase alpha (IKKα)) have long been known to play roles in promoting inflammation and tumorigenesis. However, the molecular mechanism behind these seemingly discrete functions has not been fully elucidated. A new role for IKKα in promoting metastasis in response to proinflammatory signals has now been described in Nature by Karin and colleagues. The authors found that nuclear levels of active IKKα dramatically increase in response to cytokine stimulation in prostate cancer. Nuclear IKKα then binds to and silences the Maspin promoter — which normally suppresses cellular motility — thus promoting metastasis.
Maspin (Serpinb5) — a known inhibitor of motility and metastasis — was identified as an IKKα-responsive suppressor of metastasis in a mouse model of prostate cancer. Maspin expression correlated with a loss of IKKα activation, and while robust expression was detected in primary IKKα mutant prostate tumors, Maspin was not detected in metastases of these tumors. Genetic depletion of Maspin in the IKKα mutant tumors dramatically increased metastatic potential. Similarly, overexpression of Maspin in murine prostate tumors abolished metastatic activity. Furthermore, exogenous expression of constitutively active IKKα significantly downregulated Maspin expression. These results clearly implicate Maspin as an inhibitor of metastasis, and suggest a role for IKKα in the regulation of Maspin activity. To define a role for IKKα in modulating Maspin expression, the authors performed chromatin immunoprecipitation and discovered that IKKα specifically bound to the Maspin promoter. IKKα contains a nuclear localization signal (NLS), and mutation of the NLS abrogated IKKα-mediated repression of Maspin. The levels of phosphorylated and active nuclear IKKα tightly correlated with Maspin expression: as phospho-IKKα levels increased, Maspin expression decreased. Importantly, phosphorylated and active IKKα was detected in the nucleus of human prostate cancer cells, but not their wild-type counterparts. Activated nuclear IKKα levels also correlated with progression of human prostate cancer, as high amounts of phospho-IKKα were detected in nuclear extracts of stage 4 tumors. IKKα can be activated downstream of receptor activator of the proinflammatory cytokine NF-κB ligand (RANKL) binding to RANK. Once active, IKKα can then translocate to the nucleus to bind to and silence the Maspin promoter and promote metastasis. The findings described by Karin and colleagues highlight a new role for IKKα in the nucleus, and bridge the inflammatory and metastatic roles of NF-κB in prostate oncogenesis. It will be interesting to determine if IKKα has a similar role in other solid tumors. Emily J. Chenette
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