Targeting the NF-κB pathway in estrogen receptor negative MDA-MB-231 breast cancer cells using small inhibitory RNAs

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Abstract
Cancer cells in order to survive are often mutated to block apoptosis. One chemotherapeutic option is the re-establishment of apoptosis. An example of such a therapy is the PKC inhibitor Gö6976, which activates apoptosis and shrinks in vivo tumors in estrogen receptor-negative breast cancers. We proposed as a mechanism blockage of activation of the transcription factor NF-κB, which is anti-apoptotic and often elevated in cancers. Over recent years, questions have arisen regarding the specificity of these “small-molecule inhibitors.” We have therefore explored the role of NF-κB inhibition in MDA-MB-231 breast cancer cells using small inhibitory RNAs (siRNA). siRNAs designed against NF-κB protein p65 (RelA) and IKKα, IKKβ, and IKKγ, strongly decreased the target proteins. But, unlike Gö6976, they did not decrease basal NF-κB or cause apoptosis. In particular, the decrease in p65 protein had no effects on apoptosis or cell proliferation, thus questioning the importance of NF-κB alone in the maintenance of these cells. Furthermore, the proteasome inhibitor MG-132 caused loss of IκBα, and an increase of it is phosphorylated form, but basal NF-κB was unchanged, whilst activation of NF-κB by TNFα was completely inhibited, suggesting that MG-132 activity is independent of constitutive NF-κB activation. We ascribe these differences to the specificity of inhibition by siRNAs as compared to the well-known non-specificity of small-molecule inhibitors. We conclude that the mutations in these cancer cells made them resistant to apoptosis, by elevating their NF-κB and activating other basal pathways that are blocked by Gö6976 but not by IKK and p65 siRNAs. J. Cell. Biochem. 98: 221–233, 2006.

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