Cancerous inhibitor of protein phosphatase 2A determines bortezomib-induced apoptosis in leukemia cells
Journal
Haematologica
Journal Volume
98
Journal Issue
5
Pages
729-738
Date Issued
2013
Author(s)
Abstract
The multiple cellular targets affected by proteasome inhibition implicate a potential role for bortezomib, a first-inclass 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. ? 2013 Ferrata Storti Foundation.
SDGs
Other Subjects
bortezomib; phosphoprotein phosphatase 2A; proteasome inhibitor; small interference RNA; unclassified drug; antineoplastic agent; autoantigen; boronic acid derivative; bortezomib; KIAA1524 protein, human; membrane protein; phosphoprotein phosphatase 2; proteasome; protein kinase B; pyrazine derivative; apoptosis; article; cancer inhibition; cell death; cell proliferation; cell strain K 562; disease association; down regulation; drug efficacy; drug sensitivity; enzyme linked immunosorbent assay; gene silencing; human; human cell; immunoblotting; immunohistochemistry; leukemia; Western blotting; animal; apoptosis; DNA replication; dose response; drug effects; drug resistance; drug screening; enzyme activation; gene expression regulation; genetic transcription; genetics; HL 60 cell line; K562 cell line; leukemia; metabolism; mouse; tumor cell line; Animals; Antineoplastic Agents; Apoptosis; Autoantigens; Boronic Acids; Cell Line, Tumor; DNA Replication; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Enzyme Activation; Gene Expression Regulation, Leukemic; HL-60 Cells; Humans; K562 Cells; Leukemia; Membrane Proteins; Mice; Proteasome Endopeptidase Complex; Protein Phosphatase 2; Proto-Oncogene Proteins c-akt; Pyrazines; Transcription, Genetic; Xenograft Model Antitumor Assays
Publisher
Ferrata Storti Foundation
Type
journal article