Inhibition of IκBα nuclear export as an approach to abrogate nuclear factor-κB-dependent cancer cell survival

Abstract

Deregulation of the transcription factor nuclear factor-κB (NF-κB) leading to its constitutive activation is frequently observed in human cancer. Because altered NF-κB activities often promote the survival of malignant cells, its inhibition is regarded as a promising anticancer strategy. Because activation of the latent cytoplasmic NF-κB complex can be induced by a wide variety of different stimuli, its deregulation may occur by an equally large number of distinct mechanisms. This diversity raises a conundrum in conceptualizing general approaches to attenuate NF-κB activity in cancer. Here, we provide evidence that inhibition of IκBα nuclear export is a viable target to generally abrogate constitutive NF-κB activity in different cancer cell types. We show that inhibition of IκBα nuclear export has an important course of events in cancer cells harboring constitutive NF-κB activity - an initial increase in the pool of stable nuclear NF-κB/IκBα complexes that leads to a reduction of constitutive NF-κB activity and subsequent induction of apoptosis. Importantly, similar effects on multiple different cancer cell types indicate that inhibition of nuclear export of IκBα leads to broad inhibition of constitutive NF-κB activation regardless of various deregulated, upstream events involved.