NFkappaB: a pivotal transcription factor in prostate cancer metastasis to bone.

Abstract

Prostate cancers frequently metastasize to bone and this accounts for substantial morbidity. We investigated the potential role of the transcription factor NFkappaB 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 NFkappaB signaling, otherwise absent in PC-3 cells stably expressing a mutant form of the inhibitory kappa B (IkappaB) protein alpha (PC-3.mIkappaB). 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.mIkappaB cells. Similarly, although PC-3.WT cells were invasive in a chicken chorioallantoic membrane extravasation model, PC-3.mIkappaB cells lose this capacity to invade. NFkappaB 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.mIkappaB 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.mIkappaB cells. These in vitro experiments suggest NFkappaB as an important target to prevent prostate cancer bone metastasis and provide a rationale for further study of this transcription factor in metastatic disease.