title: Cancerous inhibitor of protein phosphatase 2A determines bortezomib-induced apoptosis in leukemia cells.
abstract: The multiple cellular targets affected by proteasome inhibition implicate a potential role for bortezomib, a first-in-class proteasome inhibitor, in enhancing antitumor activities in hematologic malignancies. Here, we examined the antitumor activity and drug targets of bortezomib in leukemia cells. Human leukemia cell lines were used for in vitro studies. Drug efficacy was evaluated by apoptosis assays and associated molecular events assessed by Western Blot. Gene silencing was performed by small interference RNA. Drug was tested in vivo in xenograft models of human leukemia cell lines and in primary leukemia cells. Clinical samples were assessed by immunohistochemical staining. Bortezomib differentially induced apoptosis in leukemia cells that was independent of its proteasome inhibition. Cancerous inhibitor of protein phosphatase 2A, a cellular inhibitor of protein phosphatase 2A, mediated the apoptotic effect of bortezomib. Bortezomib increased protein phosphatase 2A activity in sensitive leukemia cells (HL-60 and KG-1), but not in resistant cells (MOLT-3 and K562). Bortezomib's downregulation of cancerous inhibitor of protein phosphatase 2A and phospho-Akt correlated with its drug sensitivity. Furthermore, cancerous inhibitor of protein phosphatase 2A negatively regulated protein phosphatase 2A activity. Ectopic expression of CIP2A up-regulated phospho-Akt and protected HL-60 cells from bortezomib-induced apoptosis, whereas silencing CIP2A overcame the resistance to bortezomib-induced apoptosis in MOLT3 and K562 cells. Importantly, bortezomib exerted in vivo antitumor activity in HL-60 xenografted tumors and induced cell death in some primary leukemic cells. Cancerous inhibitor of protein phosphatase 2A was expressed in leukemic blasts from bone marrow samples. Cancerous inhibitor of protein phosphatase 2A plays a major role in mediating bortezomib-induced apoptosis in leukemia cells.
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming Universit, Taipei, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.forename: Hsin-Yu
authors.initials: HY
authors.lastname: Kuo
authors.forename: Hsiang-Po
authors.initials: HP
authors.lastname: Huang
authors.forename: Ming-Huang
authors.initials: MH
authors.lastname: Chen
authors.forename: Cheng-Hwai
authors.initials: CH
authors.lastname: Tzeng
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001324:Autoantigens; D001897:Boronic Acids; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011719:Pyrazines; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; D046988:Proteasome Endopeptidase Complex