Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin

Abstract

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.

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

“…5 In addition to its cytoplasmic functions where it controls the activation of both classical and alternative NF-κB pathways, 6,[9][10][11][12] IKKα can function as a nuclear protein kinase, [33][34][35] and nuclear IKKα plays important roles in prostate cancer progression and metastasis. 13,14 In the present study we have shown that IKKα controls the biogenesis of a group of miRNA, including miR-196a. Phosphorylation of IKKα at 23 T site promotes the association of IKKα with pri-miRNAs, where MiR-196a has two forms: miR-196a1 and miR-196a2.…”

“…Recently, we found that IKKα can be translocated into the nucleus and nuclear IKKα plays important roles in prostate cancer progression and metastasis. 13,14 MicroRNAs (miRNAs) regulate gene expression through suppression of translation and decay of target mRNAs, and are involved in diverse physiological and pathological processes. The primary transcripts of miRNA (pri-miRNA) are cleaved into precursor miRNA (pre-miRNA) by nuclear Drosha, and further processed to mature miRNAs by cytoplasmic Dicer1 in mammalian miRNA biogenesis.…”

NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer

“…IKK-dependent but NF-κB transcription-independent function is also involved in the control of metastasis. It has been shown that genetic inhibition of IKKα kinase activity promotes Maspin expression and reduces metastatic potential of the cancer cells (Luo et al, 2007). Moreover, NF-κB is involved in angiogenesis by controlling key angiogenesis factors such as VEGF, IL-6, MCP-1 and MMPs (Schmidt et al, 2007).…”

Prostate cancer: genes, environment, immunity and the use of immunotherapy

“…[34][35][36][37] Similarly, IkB kinase-a-activation reduces the infiltration of RANK ligand-expressing inflammatory cells and is associated with metastasis of prostate cancer in mice. 38 These observations suggest a combined role of gene, environment (macro and micro) and immunity in the development of prostate cancer.…”