title: Protein phosphatase 2A as a potential target for treatment of adult T cell leukemia.
abstract: The aim of this study was to establish the role of serine/threonine protein phosphatase 2A (PP2A) in the survival of leukemic cells from patients with adult T cell leukemia (ATL), associated with human T cell leukemia virus type 1 (HTLV-1). In HTLV-1-infected T cell lines and ATL cells, okadaic acid (OkA), a potent PP2A inhibitor, induced decrease in cell viability and G₁ cell cycle arrest by decreasing the expression levels of cyclin D2, cyclin-dependent kinase 4 and cyclin-dependent kinase 6, phosphorylation of pRb, and upregulation of p21, p27 and GADD45α. OkA-induced apoptosis was also due to the suppression of expression of Bcl-2, Bcl-x(L) and XIAP, and the activation of caspases-3, -8 and -9, and caspase-3 downstream mammalian STE20-like kinase 1 and H2AX. OkA inhibited nuclear factor-kappa B DNA binding and activated mitogen-activated protein (MAP) kinases. Other new PP2A-specific inhibitors, cytostatin and rubratoxin A, also induced decrease in cell viability through caspase-dependent mechanism. MAP kinase inhibitors confirmed the role of p38 MAP kinase in PP2A inhibitors-induced apoptosis. OkA resulted in the generation of reactive oxygen species, and exogenous antioxidant prevented activation of the indicated caspases. Finally, PP2A knockdown inhibited cell growth. The results showed that PP2A inhibition caused reactive oxygen species generation and affected distinct signaling pathways, resulting in the activation of H2AX and subsequent apoptotic cell death. These results suggest that PP2A is a potentially useful target in the treatment of ATL.
authors.affiliation: Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. naokimori50@gmail.com.
authors.forename: Naoki
authors.initials: N
authors.lastname: Mori
authors.forename: Chie
authors.initials: C
authors.lastname: Ishikawa
authors.forename: Jun-Nosuke
authors.initials: JN
authors.lastname: Uchihara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yasumoto
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015490:HTLV-I Infections / Q000188:drug therapy / Q000201:enzymology / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000502:physiology; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D019319:Okadaic Acid; D054648:Protein Phosphatase 2; D020169:Caspases