RGD Reference Report - Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. - Rat Genome Database

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Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin.

Authors: Luo, JL  Tan, W  Ricono, JM  Korchynskyi, O  Zhang, M  Gonias, SL  Cheresh, DA  Karin, M 
Citation: Luo JL, etal., Nature. 2007 Apr 5;446(7136):690-4. Epub 2007 Mar 18.
RGD ID: 2298657
Pubmed: PMID:17377533   (View Abstract at PubMed)
DOI: DOI:10.1038/nature05656   (Journal Full-text)

Inflammation enhances tumour promotion through NF-kappaB-dependent mechanisms. NF-kappaB was also proposed to promote metastatogenesis through epithelial-mesenchymal transition. Yet a mechanistic link between inflammation and metastasis is missing. We identified a role for IkappaB kinase alpha (IKKalpha), activated by receptor activator of NF-kappaB (RANK/TNFRSF11A), in mammary epithelial proliferation during pregnancy. Owing to similarities between mammary and prostate epithelia, we examined IKKalpha involvement in prostate cancer and its progression. Here we show that a mutation that prevents IKKalpha activation slows down CaP growth and inhibits metastatogenesis in TRAMP mice, which express SV40 T antigen in the prostate epithelium. Decreased metastasis correlated with elevated expression of the metastasis suppressor Maspin, the ablation of which restored metastatic activity. IKKalpha activation by RANK ligand (RANKL/TNFSF11) inhibits Maspin expression in prostate epithelial cells, whereas repression of Maspin transcription requires nuclear translocation of active IKKalpha. The amount of active nuclear IKKalpha in mouse and human prostate cancer correlates with metastatic progression, reduced Maspin expression and infiltration of prostate tumours with RANKL-expressing inflammatory cells. We propose that tumour-infiltrating RANKL-expressing cells lead to nuclear IKKalpha activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Neoplasm Metastasis  ISOChuk (Mus musculus)2298657; 2298657associated with prostate adenocarcinomaRGD 
Neoplasm Metastasis  IMP 2298657associated with prostate adenocarcinomaRGD 

Objects Annotated

Genes (Rattus norvegicus)
Chuk  (component of inhibitor of nuclear factor kappa B kinase complex)

Genes (Mus musculus)
Chuk  (conserved helix-loop-helix ubiquitous kinase)

Genes (Homo sapiens)
CHUK  (component of inhibitor of nuclear factor kappa B kinase complex)


Additional Information