title: XIAP downregulation promotes caspase-dependent inhibition of proteasome activity in AML cells.
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.
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. bicarter@mdanderson.org
authors.forename: Bing Z
authors.initials: BZ
authors.lastname: Carter
authors.forename: Duncan H
authors.initials: DH
authors.lastname: Mak
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.forename: Wencai
authors.initials: W
authors.lastname: Ma
authors.forename: Po Yee
authors.initials: PY
authors.lastname: Mak
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007976:Leupeptins / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000072000:NF-KappaB Inhibitor alpha; D016376:Oligonucleotides, Antisense / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D050884:HSP72 Heat-Shock Proteins; D020672:I-kappa B Proteins; D007976:Leupeptins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C000606204:NFKBIA protein, human; D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde