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XIAP downregulation promotes caspase-dependent inhibition of proteasome activity in AML cells

Bing Z Carter1, Duncan H Mak, Zhiqiang Wang

  • 1Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. bicarter@mdanderson.org

Leukemia Research
|May 15, 2013
PubMed

Insights

In acute myeloid leukemia (AML), inhibiting XIAP increases proteasome gene expression and decreases proteasome activity. This suggests XIAP inhibition

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Hematology

Background:

  • The role of X-linked inhibitor of apoptosis protein (XIAP) in acute myeloid leukemia (AML) is not fully understood.
  • XIAP is known to have multiple functions in cellular processes.

Purpose of the Study:

  • To investigate the effect of XIAP suppression on gene expression and biological pathways in AML.
  • To elucidate the mechanisms underlying the anti-AML effects of XIAP inhibition.

Main Methods:

  • Suppression of XIAP expression using antisense oligonucleotides in AML cells.
  • Analysis of gene expression profiles and biological pathways.
  • Measurement of 20S proteasome activity.
  • Assessment of protein levels (IκBα, Mcl-1, HSP70) and the impact of pan-caspase inhibitors.

Main Results:

  • XIAP inhibition upregulated proteasome genes, similar to bortezomib or MG132.
  • XIAP suppression decreased 20S proteasome activity, an effect partially reversed by a pan-caspase inhibitor.
  • Levels of IκBα, Mcl-1, and HSP70 were increased in AML cells following XIAP inhibition.

Conclusions:

  • XIAP contributes to elevated proteasome activity in AML cells.
  • The anti-tumor effects of XIAP inhibition in AML may involve caspase-dependent proteasome inhibition.

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