Inhibition of IkappaBalpha nuclear export as an approach to abrogate nuclear factor-kappaB-dependent cancer cell survival.
Deregulation of the transcription factor nuclear factor-kappaB (NF-kappaB) leading to its constitutive activation is frequently observed in human cancer. Because altered NF-kappaB activities often promote the survival of malignant cells, its inhibition is regarded as a promising anticancer strategy. Because activation of the latent cytoplasmic NF-kappaB 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-kappaB activity in cancer. Here, we provide evidence that inhibition of IkappaBalpha nuclear export is a viable target to generally abrogate constitutive NF-kappaB activity in different cancer cell types. We show that inhibition of IkappaBalpha nuclear export has an important course of events in cancer cells harboring constitutive NF-kappaB activity-an initial increase in the pool of stable nuclear NF-kappaB/IkappaBalpha complexes that leads to a reduction of constitutive NF-kappaB activity and subsequent induction of apoptosis. Importantly, similar effects on multiple different cancer cell types indicate that inhibition of nuclear export of IkappaBalpha leads to broad inhibition of constitutive NF-kappaB activation regardless of various deregulated, upstream events involved.
O'Connor
Shelby
S
Program in Cellular and Molecular Biology, Department of Pharmacology, University of Wisconsin-Madison, 3795 Medical Sciences Center, 1300 University Avenue, Madison, WI 53706, USA.
Shumway
Stuart
S
Miyamoto
Shigeki
S
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D016296:Mutagenesis; D016297:Mutagenesis, Site-Directed; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha