NF-κB plays an important role in many types of cancer, including prostate cancer (PCa), but the role of the upstream kinase of NF-κB, IKKβ, in PCa has not been fully documented, nor are there any effective IKKβ inhibitors used in clinical settings. Here, we have shown that IKKβ activity is mediated by multiple kinases including IKKα in human PCa cell lines that express activated IKKβ. Immunohistochemical analysis (IHC) of human PCa tissue microarrays (TMA) demonstrates that phosphorylation of IKKα/β within its activation loop gradually increases in low to higher stage tumors as compared to normal tissue. The expression of cell proliferation and survival markers (Ki67, Survivin), epithelial-to-mesenchymal transition (EMT) markers (Slug, Snail), as well as cancer stem cell (CSC) related transcription factors (Nanog, Sox2, Oct-4), also increase in parallel among the respective TMA samples analyzed. IKKβ, but not NF-κB, is found to regulate Nanog, which, in turn, modulates the levels of Oct4, Sox2, Snail and Slug, indicating an essential role of IKKβ in regulating cancer stem cells and EMT. The novel IKKβ inhibitor CmpdA inhibits constitutively activated IKKβ/NF-κB signaling, leading to induction of apoptosis and inhibition of proliferation, migration and stemness in these cells. CmpdA also significantly inhibits tumor growth in xenografts without causing apparent in vivo toxicity. Furthermore, CmpdA and docetaxel act synergistically to inhibit proliferation of PCa cells. These results indicate that IKKβ plays a pivotal role in PCa, and targeting IKKβ, including in combination with docetaxel, may be a potentially useful strategy for treating advanced PCa.
Molecular cancer therapeutics. 2016 Apr 08 [Epub ahead of print]
Yanting Zhang, Rena G Lapidus, Peiyan Liu, Eun Yong Choi, Samusi Adediran, Arif Hussain, Xinghuan Wang, Xuefeng Liu, Han C Dan
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine., Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine., Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine., Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine., Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine., Baltimore VA Medical Center., Department of Urology, Zhongnan Hospital of Wuhan University., Department of Pathology, Georgetown University Medical Center., Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine .