Targeting IκB Kinase β/NF-κB Signaling in Human Prostate Cancer by a Novel IκB Kinase β Inhibitor CmpdA.
Targeting IκB Kinase β/NF-κB Signaling in Human Prostate Cancer by a Novel IκB Kinase β Inhibitor CmpdA.
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DOI：
10.1158/1535-7163.mct-15-0999
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发表时间：
2016-07
影响因子：
5.7
通讯作者：
Dan HC
中科院分区：
文献类型：
--
作者：
Zhang Y;Lapidus RG;Liu P;Choi EY;Adediran S;Hussain A;Wang X;Liu X;Dan HC
NF-κB 在包括前列腺癌 (PCa) 在内的多种癌症中发挥着重要作用，但 NF-κB 上游激酶 IKKβ 在 PCa 中的作用尚未得到充分证明，也没有任何有效的 IKKβ 抑制剂用于临床。在这里，我们发现 IKKβ 活性是由表达活化 IKKβ 的人 PCa 细胞系中的多种激酶（包括 IKKα）介导的。人 PCa 组织微阵列 (TMA) 的免疫组织化学分析 (IHC) 表明，与正常组织相比，在低期到高期肿瘤中，IKKα/β 在其激活环内的磷酸化逐渐增加。细胞增殖和存活标记物（Ki67、Survivin）、上皮间质转化（EMT）标记物（Slug、Snail）以及癌症干细胞（CSC）相关转录因子（Nanog、Sox2、Oct-4）的表达在分析的各个 TMA 样本中也平行增加。研究发现 IKKβ（而非 NF-κB）可以调节 Nanog，而 Nanog 反过来又调节 Oct4、Sox2、Snail 和 Slug 的水平，表明 IKKβ 在调节癌症干细胞和 EMT 中发挥重要作用。新型 IKKβ 抑制剂 CmpdA 抑制持续激活的 IKKβ/NF-κB 信号传导，从而诱导细胞凋亡并抑制这些细胞的增殖、迁移和干性。 CmpdA 还显着抑制异种移植物中的肿瘤生长，而不引起明显的体内毒性。此外，CmpdA 和多西他赛协同作用抑制 PCa 细胞的增殖。这些结果表明 IKKβ 在 PCa 中发挥着关键作用，靶向 IKKβ（包括与多西他赛联合）可能是治疗晚期 PCa 的潜在有用策略。
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.