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 journalArticle

Abstract

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)
JournalAmerican Journal of Physiology - Cell Physiology
Volume286
Issue number5 55-5
DOIs
StatePublished - May 2004
Externally publishedYes

Fingerprint

Polyamines
Epithelial Cells
Apoptosis
Caspase 3
Inhibitor of Apoptosis Proteins
Cycloheximide
Tumor Necrosis Factor-alpha
X-Linked Inhibitor of Apoptosis Protein
Eflornithine
Maintenance

Keywords

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

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

NF-κB-mediated IAP expression induces resistance of intestinal epithelial cells to apoptosis after polyamine depletion. / Zou, Tongtong; Rao, Jaladanki N.; Guo, Xin; Liu, Lan; Zhang, Huifang M.; Strauch, Eric D.; Bass, Barbara L.; Wang, Jian Ying.

In: American Journal of Physiology - Cell Physiology, Vol. 286, No. 5 55-5, 05.2004.

Research output: Contribution to journalArticle

Zou, Tongtong ; Rao, Jaladanki N. ; Guo, Xin ; Liu, Lan ; Zhang, Huifang M. ; Strauch, Eric D. ; Bass, Barbara L. ; Wang, Jian Ying. / NF-κB-mediated IAP expression induces resistance of intestinal epithelial cells to apoptosis after polyamine depletion. In: American Journal of Physiology - Cell Physiology. 2004 ; Vol. 286, No. 5 55-5.
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T1 - NF-κB-mediated IAP expression induces resistance of intestinal epithelial cells to apoptosis after polyamine depletion

AU - Zou, Tongtong

AU - Rao, Jaladanki N.

AU - Guo, Xin

AU - Liu, Lan

AU - Zhang, Huifang M.

AU - Strauch, Eric D.

AU - Bass, Barbara L.

AU - Wang, Jian Ying

PY - 2004/5

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N2 - 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.

AB - 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.

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KW - Caspase-3

KW - Growth arrest

KW - IκB

KW - Intestinal epithelium

KW - Ornithine decarboxylase

KW - Programmed cell death

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