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

Tongtong Zou, Jaladanki N. Rao, Xin Guo, Lan Liu, Huifang M. Zhang, Eric D. Strauch, Barbara L. Bass, Jian Ying Wang

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


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)-κB activity in normal intestinal epithelial (IEC-6) cells and that polyamine depletion activates NF-κB 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-κB and play a role in antiapoptotic activity of polyamine depletion in IEC-6 cells. Depletion of cellular polyamines by α -difluoromethylornithine not only activated NF-κB activity but also increased expression of c-IAP2 and XIAP. Specific inhibition of NF-κB by the recombinant adenoviral vector containing IκBα superrepressor (AdIκBSR) prevented the induction of c-IAP2 and XIAP in polyamine-deficient cells. Decreased levels of c-IAP2 and XIAP proteins by inactivation of NF-κB through AdIκBSR 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)-α 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-κB in intestinal epithelial cells. Increased c-IAP2 and XIAP after polyamine depletion induce the resistance to TNF-α/CHX-induced apoptosis, at least partially, through inhibition of the caspase-3 activity.

Original languageEnglish (US)
Pages (from-to)C1009-C1018
JournalAmerican Journal of Physiology - Cell Physiology
Issue number5 55-5
StatePublished - May 2004


  • α-difluoromethylornithine
  • Caspase-3
  • Growth arrest
  • IκB
  • Intestinal epithelium
  • Ornithine decarboxylase
  • Programmed cell death

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology


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