Protein Phosphatase 2A as a Potential Target for Treatment of Adult T Cell Leukemia

E-ISSN： 1873-5576|13|8|829-842

ISSN： 1568-0096

Source： Current Cancer Drug Targets, Vol.13, Iss.8, 2013-10, pp. : 829-842

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Abstract

The aim of this study was to establish the role of serine/threonine protein phosphatase 2A (PP2A) in thesurvival of leukemic cells from patients with adult T cell leukemia (ATL), associated with human T cell leukemia virustype 1 (HTLV-1). In HTLV-1-infected T cell lines and ATL cells, okadaic acid (OkA), a potent PP2A inhibitor, induceddecrease in cell viability and G₁ cell cycle arrest by decreasing the expression levels of cyclin D2, cyclin-dependent kinase4 and cyclin-dependent kinase 6, phosphorylation of pRb, and upregulation of p21, p27 and GADD45#945;. OkA-inducedapoptosis was also due to the suppression of expression of Bcl-2, Bcl-x_L and XIAP, and the activation of caspases-3, -8and -9, and caspase-3 downstream mammalian STE20-like kinase 1 and H2AX. OkA inhibited nuclear factor-kappa BDNA binding and activated mitogen-activated protein (MAP) kinases. Other new PP2A-specific inhibitors, cytostatin andrubratoxin A, also induced decrease in cell viability through caspase-dependent mechanism. MAP kinase inhibitorsconfirmed the role of p38 MAP kinase in PP2A inhibitors-induced apoptosis. OkA resulted in the generation of reactiveoxygen species, and exogenous antioxidant prevented activation of the indicated caspases. Finally, PP2A knockdowninhibited cell growth. The results showed that PP2A inhibition caused reactive oxygen species generation and affecteddistinct signaling pathways, resulting in the activation of H2AX and subsequent apoptotic cell death. These results suggestthat PP2A is a potentially useful target in the treatment of ATL.