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GROWTH, DIFFERENTIATION, AND APOPTOSIS

NF-B-mediated IAP expression induces resistance of intestinal epithelial cells to apoptosis after polyamine depletion

Departments of ¹Surgery and ²Pathology, University of Maryland School of Medicine and ³Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201

Submitted 3 November 2003 ; accepted in final form 10 December 2003

Apoptosis plays a crucial role in maintenance of intestinal epithelial integrity and is highly regulated by numerous factors, including cellular polyamines. We recently showed that polyamines regulate nuclear factor (NF)-B activity in normal intestinal epithelial (IEC-6) cells and that polyamine depletion activates NF-B and promotes resistance to apoptosis. The current study went further to determine whether the inhibitors of apoptosis (IAP) family of proteins, c-IAP2 and XIAP, are downstream targets of activated NF-B and play a role in antiapoptotic activity of polyamine depletion in IEC-6 cells. Depletion of cellular polyamines by -difluoromethylornithine not only activated NF-B activity but also increased expression of c-IAP2 and XIAP. Specific inhibition of NF-B by the recombinant adenoviral vector containing IB superrepressor (AdIBSR) prevented the induction of c-IAP2 and XIAP in polyamine-deficient cells. Decreased levels of c-IAP2 and XIAP proteins by inactivation of NF-B through AdIBSR infection or treatment with the specific inhibitor Smac also overcame the resistance of polyamine-depleted cells to apoptosis induced by the combination of tumor necrosis factor (TNF)- and cycloheximide (CHX). Although polyamine depletion did not alter levels of procaspase-3 protein, it inhibited formation of the active caspase-3. Decreased levels of c-IAP2 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-IAP2 and XIAP by activating NF-B in intestinal epithelial cells. Increased c-IAP2 and XIAP after polyamine depletion induce the resistance to TNF-/CHX-induced apoptosis, at least partially, through inhibition of the caspase-3 activity.

programmed cell death; growth arrest; ornithine decarboxylase; IB; caspase-3; -difluoromethylornithine; intestinal epithelium

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