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

被引:2
作者
Mori, Naoki [1 ]
Ishikawa, Chie [1 ,2 ]
Uchihara, Jun-Nosuke [3 ]
Yasumoto, Takeshi [4 ]
机构
[1] Univ Ryukyus, Grad Sch Med, Dept Microbiol & Oncol, Nishihara, Okinawa 9030215, Japan
[2] Univ Ryukyus, Transdisciplinary Res Org Subtrop & Isl Studies, Nishihara, Okinawa 9030213, Japan
[3] Naha City Hosp, Dept Hematol, Naha, Okinawa 9028511, Japan
[4] Okinawa Sci & Technol Promot Ctr, Marine Bio Ind Div, Naha, Okinawa 9000029, Japan
关键词
Adult T cell leukemia; H2AX; human T cell leukemia virus type 1; nuclear factor-kappa B; okadaic acid; protein phosphatase 2A; reactive oxygen species; NF-KAPPA-B; VIRUS TYPE-I; ONCOGENE PRODUCT TAX; CYCLE PROGRESSION; HISTONE H2AX; HTLV-I; INDUCED APOPTOSIS; OXIDATIVE STRESS; GENE-EXPRESSION; MYELOMA CELLS;
D O I
暂无
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 G(1) 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 GADD45 alpha. 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.
引用
收藏
页码:829 / 842
页数:14
相关论文
共 57 条
[1]   ISOLATION OF INTACT NUCLEI FROM HEMATOPOIETIC-CELL TYPES [J].
ANTALIS, TM ;
GODBOLT, D .
NUCLEIC ACIDS RESEARCH, 1991, 19 (15) :4301-4301
[2]  
Bononi A., 2011, ENZYME RES, V2011, P26, DOI DOI 10.4061/2011/329098
[3]   Apoptosis induced by protein phosphatase 2A (PP2A) inhibition in T leukemia cells is negatively regulated by PP2A-associated p38 mitogen-activated protein kinase [J].
Boudreau, Robert M. ;
Conrad, David M. ;
Hoskin, David W. .
CELLULAR SIGNALLING, 2007, 19 (01) :139-151
[4]   Differential involvement of reactive oxygen species in apoptosis caused by the inhibition of protein phosphatase 2A In Jurkat and CCRF-CEM human T-leukemia cells [J].
Boudreau, Robert T. M. ;
Conrad, David M. ;
Hoskin, David W. .
EXPERIMENTAL AND MOLECULAR PATHOLOGY, 2007, 83 (03) :347-356
[5]  
Castigli E, 2006, ONCOL REP, V15, P463
[6]   Oxidative stress induces the expression of Fas and Fas ligand and apoptosis in murine intestinal epithelial cells [J].
Denning, TL ;
Takaishi, H ;
Crowe, SE ;
Boldogh, I ;
Jevnikar, A ;
Ernst, PB .
FREE RADICAL BIOLOGY AND MEDICINE, 2002, 33 (12) :1641-1650
[7]   A cytokine-responsive I kappa B kinase that activates the transcription factor NF-kappa B [J].
DiDonato, JA ;
Hayakawa, M ;
Rothwarf, DM ;
Zandi, E ;
Karin, M .
NATURE, 1997, 388 (6642) :548-554
[8]   Both phosphorylation and caspase-mediated cleavage contribute to regulation of the Ste20-like protein kinase Mst1 during CD95/Fas-induced apoptosis [J].
Graves, JD ;
Draves, KE ;
Gotoh, Y ;
Krebs, EG ;
Clark, EA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (18) :14909-14915
[9]   Shared principles in NF-κB signaling [J].
Hayden, Matthew S. ;
Ghosh, Sankar .
CELL, 2008, 132 (03) :344-362
[10]   ADULT T-CELL LEUKEMIA - ANTIGEN IN AN ATL CELL-LINE AND DETECTION OF ANTIBODIES TO THE ANTIGEN IN HUMAN-SERA [J].
HINUMA, Y ;
NAGATA, K ;
HANAOKA, M ;
NAKAI, M ;
MATSUMOTO, T ;
KINOSHITA, KI ;
SHIRAKAWA, S ;
MIYOSHI, I .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1981, 78 (10) :6476-6480