Krishnamurthy Soumya, Basu Alakananda
University of North Texas Health Science Center, Fort Worth, TX, USA.
Genes Cancer. 2011 Nov;2(11):1044-50. doi: 10.1177/1947601912444604.
The inhibitor of κ B kinase-ε (IKKε), a breast cancer oncogene, functions as a transforming kinase by activating NF-κB. IKKε is often elevated in breast cancers in the absence of any gene amplification. Because Akt-mediated transformation was shown to require IKKε, we examined if Akt regulates IKKε level in breast cancer cells. Knockdown of Akt2, but not other Akt isoforms, decreased the basal and TNF-induced IKKε protein and mRNA level, and overexpression of Akt2 in MDA-MB-231 cells increased IKKε level. The decrease in IKKε level by Akt2 knockdown was not only restricted to MDA-MB-231 cells but was also observed in several other breast cancer cells, including HCC1937 and MCF-10CA1a cells. Knockdown of p65/RelA subunit of NF-κB decreased IKKε level and attenuated the increase in IKKε caused by Akt2 overexpression, suggesting that Akt2-mediated induction of IKKε involves NF-κB activation. Silencing of IKKε also decreased long-term clonogenic survival of Akt2-overexpressing MDA-MB-231 cells. Taken together, these results demonstrate for the first time that IKKε functions downstream of Akt2 to promote breast cancer cell survival.
κB激酶ε（IKKε）是一种乳腺癌致癌基因，它通过激活核因子κB（NF-κB）发挥转化激酶的作用。在没有任何基因扩增的情况下，IKKε在乳腺癌中常常升高。由于已表明Akt介导的转化需要IKKε，我们研究了Akt是否调节乳腺癌细胞中的IKKε水平。敲低Akt2而非其他Akt亚型，可降低基础状态和肿瘤坏死因子（TNF）诱导的IKKε蛋白及mRNA水平，在MDA-MB-231细胞中过表达Akt2可提高IKKε水平。敲低Akt2导致的IKKε水平降低不仅局限于MDA-MB-231细胞，在其他几种乳腺癌细胞中也有观察到，包括HCC1937和MCF-10CA1a细胞。敲低NF-κB的p65/RelA亚基可降低IKKε水平，并减弱Akt2过表达引起的IKKε增加，这表明Akt2介导的IKKε诱导涉及NF-κB激活。沉默IKKε也降低了过表达Akt2的MDA-MB-231细胞的长期克隆存活能力。综上所述，这些结果首次证明IKKε在Akt2下游发挥作用以促进乳腺癌细胞存活。
