Targeting IκB Kinase β/NF-κB Signaling in Human Prostate Cancer by a Novel IκB Kinase β Inhibitor CmpdA

NF-kappa B plays an important role in many types of cancer, including prostate cancer, but the role of the upstream kinase of NF-kappa B, IKK beta, in prostate cancer has neither been fully documented nor are there any effective IKK beta inhibitors used in clinical settings. Here, we have shown that IKK beta activity is mediated by multiple kinases including IKK alpha in human prostate cancer cell lines that express activated IKK beta. IHC analysis (IHC) of human prostate cancer tissue microarrays (TMA) demonstrates that phosphorylation of IKK alpha/beta within its activation loop gradually increases in low to higher stage tumors as compared with normal tissue. The expression of cell proliferation and survival markers (Ki-67, Survivin) and 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. IKK beta, but not NF-kappa B, is found to regulate Nanog, which, in turn, modulates the levels of Oct4, Sox2, Snail, and Slug, indicating an essential role of IKK beta in regulating CSCs and EMT. The novel IKK beta inhibitor CmpdA inhibits constitutively activated IKK beta/NF-kappa B 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 prostate cancer cells. These results indicate that IKK beta plays a pivotal role in prostate cancer, and targeting IKK beta, including in combination with docetaxel, may be a potentially useful strategy for treating advanced prostate cancer. (C) 2016 AACR.