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Signaling and Regulation

Inhibition of IB Nuclear Export as an Approach to Abrogate Nuclear Factor-B–Dependent Cancer Cell Survival ¹

Program in Cellular and Molecular Biology, Department of Pharmacology, University of Wisconsin-Madison, Madison, Wisconsin

Requests for reprints: Shigeki Miyamoto, Program in Cellular and Molecular Biology, Department of Pharmacology, University of Wisconsin-Madison, 3795 Medical Sciences Center, 1300 University Avenue, Madison, WI 53706. Phone: 608-262-9281; Fax: 608-262-1257. E-mail: smiyamot{at}wisc.edu

Deregulation of the transcription factor nuclear factor-B (NF-B) leading to its constitutive activation is frequently observed in human cancer. Because altered NF-B activities often promote the survival of malignant cells, its inhibition is regarded as a promising anticancer strategy. Because activation of the latent cytoplasmic NF-B 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-B activity in cancer. Here, we provide evidence that inhibition of IB nuclear export is a viable target to generally abrogate constitutive NF-B activity in different cancer cell types. We show that inhibition of IB nuclear export has an important course of events in cancer cells harboring constitutive NF-B activity—an initial increase in the pool of stable nuclear NF-B/IB complexes that leads to a reduction of constitutive NF-B activity and subsequent induction of apoptosis. Importantly, similar effects on multiple different cancer cell types indicate that inhibition of nuclear export of IB leads to broad inhibition of constitutive NF-B activation regardless of various deregulated, upstream events involved.

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