TY - JOUR
T1 - Targeting Ikβ kinase b/NF-κB signaling in human prostate cancer by a novel IκB kinase β inhibitor CmpdA
AU - Zhang, Yanting
AU - Lapidus, Rena G.
AU - Liu, Peiyan
AU - Choi, Eun Yong
AU - Adediran, Samusi
AU - Hussain, Arif
AU - Wang, Xinghuan
AU - Liu, Xuefeng
AU - Dan, Han C.
N1 - Funding Information:
This work was supported, in part, by NIH Grant R00CA149178 and startup funds from Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine (to H.C. Dan) and a Merit Review Award, Department of Veterans Affairs (to A. Hussain).
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/7
Y1 - 2016/7
N2 - NF-kB plays an important role in many types of cancer, including prostate cancer, but the role of the upstream kinase of NF-kB, IKKb, 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-kB, is found to regulate Nanog, which, in turn, modulates the levels of Oct4, Sox2, Snail, and Slug, indicating an essential role of IKKb in regulating CSCs and EMT. The novel IKKβ inhibitor CmpdA inhibits constitutively activated IKKb/NF-kB 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.
AB - NF-kB plays an important role in many types of cancer, including prostate cancer, but the role of the upstream kinase of NF-kB, IKKb, 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-kB, is found to regulate Nanog, which, in turn, modulates the levels of Oct4, Sox2, Snail, and Slug, indicating an essential role of IKKb in regulating CSCs and EMT. The novel IKKβ inhibitor CmpdA inhibits constitutively activated IKKb/NF-kB 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.
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U2 - 10.1158/1535-7163.MCT-15-0999
DO - 10.1158/1535-7163.MCT-15-0999
M3 - Article
C2 - 27196761
AN - SCOPUS:84979656464
SN - 1535-7163
VL - 15
SP - 1504
EP - 1514
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 7
ER -