Regulation of IKK  Expression by Akt2 Isoform

Abstract

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.

Implications of Akt2/Twist crosstalk on breast cancer metastatic outcome

“…These findings further reinforce the importance of the Akt2/mTOR/p70S6K axis in energy metabolism and, therefore, in cell proliferation and maintenance [26]. Akt2, unlike other isoforms, has also been reported to be involved in the upregulation of IKKe levels (a transforming kinase frequently elevated in BC) in MDA-MB-231 cells by activating the transcription factor nuclear factor (NF)-kB, resulting in cell survival [27].…”

“…Furthermore, silencing expression of Akt2 might constitute an attractive strategy for therapeutic application, as may be inferred from the results of studies based on the knockdown of this isoform through RNAi-based technology [22,23,26,27,30,31,50]. In fact, for other solid tumors, the use of miRNA-203 in p53-mutated colon cancer cells led to the downregulation of Akt2 expression in vitro, overcoming chemoresistance to paclitaxel [54].…”

IκB kinase ɛ (IKKɛ): A therapeutic target in inflammation and cancer

“…For instance, several breast cancer cell lines and $30% of primary human breast tumors express high levels of IKKe [66]. Increased IKKe expression is due to an up till now unknown mutation regulating IKKe transcript levels or to an amplification of the 1q32 region comprising the IKBKE locus [67,68]. Ectopic expression of IKKe in immortalized mammary epithelial cells at levels found in human cancer cells renders them tumorigenic, confirming that the allele amplified in breast cancer specimens is transforming [67].…”

Diallyl disulfide inhibits TNFα induced CCL2 release through MAPK/ERK and NF-Kappa-B signaling

“…The effect of DADS in this study, did not appear to involve mRNA of NFκB, but possibly reduced TNFRSF1A gene and adaptor protein tumor necrosis factor receptor (TNFR-associated death domain, TRADD), which are well known to “activate” via altering subcellular localization of NFκB. [51–53] Future research will be required to evaluate if the effects of DADS on CCL2 occur due to upstream events including TNFR down-regulation or potential involvement of AKT, which directly leads to up regulation of IKKε protein expression in MDA-MB-231 cells [54]. …”