Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan.
Curr Cancer Drug Targets. 2013 Oct;13(8):829-42. doi: 10.2174/156800961131300093.
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.
本研究旨在探讨丝氨酸/苏氨酸蛋白磷酸酶 2A（PP2A）在与人类 T 细胞白血病病毒 1（HTLV-1）相关的成人 T 细胞白血病（ATL）患者白血病细胞存活中的作用。在 HTLV-1 感染的 T 细胞系和 ATL 细胞中，强效的 PP2A 抑制剂冈田酸（OkA）通过降低 cyclin D2、CDK4 和 CDK6 的表达水平、pRb 的磷酸化以及上调 p21、p27 和 GADD45α，导致细胞活力下降和 G₁ 细胞周期停滞。OkA 诱导的细胞凋亡还归因于抑制 Bcl-2、Bcl-x(L) 和 XIAP 的表达以及激活 caspase-3、-8 和 -9，以及 caspase-3 下游哺乳动物 STE20 样激酶 1 和 H2AX。OkA 抑制核因子-κB DNA 结合并激活丝裂原激活蛋白（MAP）激酶。其他新型的 PP2A 特异性抑制剂，细胞松弛素和 rubratoxin A，也通过 caspase 依赖性机制诱导细胞活力下降。MAP 激酶抑制剂证实了 p38 MAP 激酶在 PP2A 抑制剂诱导的细胞凋亡中的作用。OkA 导致活性氧的产生，外源性抗氧化剂可防止所指示的半胱氨酸蛋白酶的激活。最后，PP2A 敲低抑制细胞生长。结果表明，PP2A 抑制导致活性氧的产生，并影响不同的信号通路，导致 H2AX 的激活和随后的细胞凋亡。这些结果表明，PP2A 是治疗 ATL 的一个有潜力的靶点。
