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.
|Journal||Clinical orthopaedics and related research|
|Issue number||415 SUPPL.|
|State||Published - Oct 2003|