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

• Published in: Leukemia research Vol. 37; no. 8; pp. 974 - 979
• Main Authors: Carter, Bing Z, Mak, Duncan H, Wang, Zhiqiang, Ma, Wencai, Mak, Po Yee, Andreeff, Michael, Davis, R. Eric
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2013
• Subjects: AML; Antineoplastic Agents - pharmacology; Apoptosis - genetics; Blotting, Western; Boronic Acids - pharmacology; Bortezomib; Caspase; Caspases - genetics; Caspases - metabolism; Cell Line, Tumor; Cell Survival - genetics; Down-Regulation; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Hematology, Oncology and Palliative Medicine; HL-60 Cells; HSP72 Heat-Shock Proteins - genetics; HSP72 Heat-Shock Proteins - metabolism; Humans; I-kappa B Proteins - genetics; I-kappa B Proteins - metabolism; IκBα; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Leupeptins - pharmacology; Myeloid Cell Leukemia Sequence 1 Protein; NF-KappaB Inhibitor alpha; Oligonucleotides, Antisense - genetics; Oligopeptides - pharmacology; Proteasome; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pyrazines - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; X-Linked Inhibitor of Apoptosis Protein - genetics; X-Linked Inhibitor of Apoptosis Protein - metabolism; XIAP; AML; Caspase; XIAP; Gene expression; Proteasome; IκBα
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2013.04.018

Abstract To further understand the role of XIAP in acute myeloid leukemia (AML), we suppressed XIAP expression by antisense oligonucleotides and determined the effect on gene expression profiles and biological pathways. XIAP inhibition upregulated expression of proteasome genes in a manner similar to the proteasome inhibitor bortezomib or MG132; decreased 20S proteasome activity, an effect which was diminished in the presence of a pan-caspase inhibitor; and increased IκBα, Mcl-1, and HSP70 in AML cells. In addition to multiple functions already described, XIAP contributes to increased proteasome activity in AML cells, and the antitumor effect of XIAP inhibition may be mediated in part through caspase-dependent proteasome inhibition.