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Am J Physiol Cell Physiol (December 18, 2003). doi:10.1152/ajpcell.00480.2003
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Submitted on November 3, 2003
Accepted on December 10, 2003

NF-{kappa}B-Mediated IAP Expression Induces Resistance of Intestinal Epithelial Cells to Apoptosis after Polyamine Depletion

Tongtong Zou1, Jaladanki N Rao1, Xin Guo1, Lan Liu1, Huifang M Zhang1, Eric D Strauch1, Barbara L Bass1, and Jian-Ying Wang1*

1 Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA

* To whom correspondence should be addressed. E-mail: jwang{at}smail.umaryland.edu.

Apoptosis plays a crucial role in maintenance of intestinal epithelial integrity and is highly regulated by numerous factors including cellular polyamines. We have recently shown that polyamines regulate NF-{kappa}B activity in normal intestinal epithelial (IEC-6) cells and that polyamine depletion activates NF-{kappa}B and promotes the resistance to apoptosis. The current study went further to determine whether the inhibitor of apoptosis (IAP) family of proteins, c-IAP2 and XIAP, are downstream targets of activated NF-{kappa}B and play a role in the anti-apoptotic activity of polyamine depletion in IEC-6 cells. Depletion of cellular polyamines by {alpha}-difluoromethylornithine (DFMO) not only activated NF-{kappa}B activity but also increased expression of c-IAP2 and XIAP proteins. Specific inhibition of NF-{kappa}B by the recombinant adenoviral vector containing I{kappa}Ba super-repressor (AdI{kappa}BSR) prevented the induction of c-IAP2 and XIAP proteins in polyamine-deficient cells. Decreased levels of c-IAP2 and XIAP proteins by inactivation of NF-{kappa}B through AdI{kappa}BSR infection or by treatment with the specific inhibitor Smac also overcame the resistance of polyamine-depleted cells to apoptosis induced by the combination of tumor necrosis factor-{alpha} (TNF-{alpha}) and cycloheximide (CHX). Although polyamine depletion did not alter levels of procaspase-3 protein, it inhibited the formation of the active caspase-3. Decreased c-IAP and XIAP by Smac prevented the inhibitory effect of polyamine depletion on the cleavage of procaspase-3 to the active caspase-3. These results indicate that polyamine depletion increases expression of c-IAP and XIAP by activating NF-{kappa}B in intestinal epithelial cells. Increased c-IAP2 and XIAP proteins following polyamine depletion induce the resistance to TNF-{alpha}/CHX-induced apoptosis, at least partially, through the inhibition of the caspase-3 activity.




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