NFκB: A Pivotal Transcription Factor in Prostate Cancer Metastasis to Bone

Prostate cancers frequently metastasize to bone and this accounts for substantial morbidity. We investigated the potential role of the transcription factor NFκB as a central regulator of prostate cancer metastasis using the prostate adenocarcinoma cell line, PC-3, in a series of in vitro studies. Wild type PC-3 cells (PC-3.WT) have high basal levels of NFκB signaling, otherwise absent in PC-3 cells stably expressing a mutant form of the inhibitory kappa B (IκB) protein alpha (PC-3.mIκB). Although PC-3. WT cells in co-culture with rat bone marrow cells enhance bone resorption, no increase was observed in co-cultures with PC-3.mIκB cells. Similarly, although PC-3.WT cells were invasive in a chicken chorioallantoic membrane extravasation model, PC-3.mIκB cells lose this capacity to invade. NFκB reciprocally regulated genes involved in cellular invasion, with upregulation of MMP-9 and downregulation of its inhibitor, TIMP-1 in PC-3.WT cells, whereas MMP-9 was downregulated and TIMP-1 was upregulated in PC-3.mIκB cells. Finally, high basal gene and protein expression of the osteoclast-activating cytokine IL-6, observed in PC-3.WT cells, was absent in PC-3.mIκB cells. These in vitro experiments suggest NFKB as an important target to prevent prostate cancer bone metastasis and provide a rationale for additional study of this transcription factor in metastatic disease.