Targeting Ikβ kinase b/NF-κB signaling in human prostate cancer by a novel IκB kinase β inhibitor CmpdA

Yanting Zhang, Rena G. Lapidus, Peiyan Liu, Eun Yong Choi, Samusi Adediran, Arif Hussain, Xinghuan Wang, Xuefeng Liu, Han C. Dan

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1504-1514
Number of pages11
JournalMolecular cancer therapeutics
Volume15
Issue number7
DOIs
StatePublished - Jul 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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