Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin.
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.
Luo
Jun-Li
JL
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA.
Tan
Wei
W
Ricono
Jill M
JM
Korchynskyi
Olexandr
O
Zhang
Ming
M
Gonias
Steven L
SL
Cheresh
David A
DA
Karin
Michael
M
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000172:deficiency / Q000235:genetics; D015843:Serpins / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D053219:Receptors, Tumor Necrosis Factor, Member 25; C085344:SERPIN-B5; D015843:Serpins; C506034:Tnfrsf25 protein, mouse; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase