STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells

Biochem J. 2005 Dec 1;392(Pt 2):335-44. doi: 10.1042/BJ20050465.


Activation of STAT3 (signal transducer and activator of transcription 3) plays a crucial role in cell survival and proliferation. The aim of the present study was to clarify the role of STAT3 signalling in the protection of polyamine-depleted intestinal epithelial cells against TNF-alpha (tumour necrosis factor-alpha)-induced apoptosis. Polyamine depletion by DFMO (alpha-difluoromethylornithine) caused phosphorylation of STAT3 at Tyr-705 and Ser-727. Phospho-Tyr-705 STAT3 was immunolocalized at the cell periphery and nucleus, whereas phospho-Ser-727 STAT3 was predominantly detected in the nucleus of polyamine-depleted cells. Sustained phosphorylation of STAT3 at tyrosine residues was observed in polyamine-depleted cells after exposure to TNF-alpha. Inhibition of STAT3 activation by AG490 or cell-membrane-permeant inhibitory peptide (PpYLKTK; where pY represents phospho-Tyr) increased the sensitivity of polyamine-depleted cells to apoptosis. Expression of DN-STAT3 (dominant negative-STAT3) completely eliminated the protective effect of DFMO against TNF-alpha-induced apoptosis. Polyamine depletion increased mRNA and protein levels for Bcl-2, Mcl-1 (myeloid cell leukaemia-1) and c-IAP2 (inhibitor of apoptosis protein-2). Significantly higher levels of Bcl-2 and c-IAP2 proteins were observed in polyamine-depleted cells before and after 9 h of TNF-alpha treatment. Inhibition of STAT3 by AG490 and DN-STAT3 decreased Bcl-2 promoter activity. DN-STAT3 decreased mRNA and protein levels for Bcl-2, Mcl-1 and c-IAP2 in polyamine-depleted cells. siRNA (small interfering RNA)-mediated inhibition of Bcl-2, Mcl-1 and c-IAP2 protein levels increased TNF-alpha-induced apoptosis. DN-STAT3 induced the activation of caspase-3 and PARP [poly(ADP-ribose) polymerase] cleavage in polyamine-depleted cells. These results suggest that activation of STAT3 in response to polyamine depletion increases the transcription and subsequent expression of anti-apoptotic Bcl-2 and IAP family proteins and thereby promotes survival of cells against TNF-alpha-induced apoptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis* / drug effects
  • Apoptosis* / genetics
  • Caspase 3
  • Caspases / metabolism
  • Cell Line
  • Eflornithine / pharmacology
  • Enzyme Activation
  • Inhibitor of Apoptosis Proteins / genetics*
  • Inhibitor of Apoptosis Proteins / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Polyamines / metabolism*
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA Interference
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation


  • Inhibitor of Apoptosis Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Polyamines
  • Proto-Oncogene Proteins c-bcl-2
  • STAT3 Transcription Factor
  • Tumor Necrosis Factor-alpha
  • Caspase 3
  • Caspases
  • Eflornithine