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Mol Cancer Ther. 2016 Jul;15(7):1504-14. doi: 10.1158/1535-7163.MCT-15-0999. Epub 2016 Apr 8.

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

Author information

1
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.
2
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland. Baltimore VA Medical Center, Baltimore, Maryland.
3
Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China.
4
Department of Pathology, Georgetown University Medical Center, Washington, DC.
5
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland. Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland. HDan@som.umaryland.edu.

Abstract

NF-κB plays an important role in many types of cancer, including prostate cancer, but the role of the upstream kinase of NF-κB, IKKβ, in prostate cancer has neither 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 prostate cancer cell lines that express activated IKKβ. IHC analysis (IHC) of human prostate cancer tissue microarrays (TMA) demonstrates that phosphorylation of IKKα/β 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. 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 CSCs 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 prostate cancer cells. These results indicate that IKKβ plays a pivotal role in prostate cancer, and targeting IKKβ, including in combination with docetaxel, may be a potentially useful strategy for treating advanced prostate cancer. Mol Cancer Ther; 15(7); 1504-14.

PMID:
27196761
PMCID:
PMC4936938
DOI:
10.1158/1535-7163.MCT-15-0999
[Indexed for MEDLINE]
Free PMC Article

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