Coordinate involvement of cell cycle arrest and apoptosis strengthen the effect of FTY720

被引:27
作者
Nagahara, Y
Matsuoka, Y
Saito, K
Ikekita, M
Higuchi, S
Shinomiya, T
机构
[1] Natl Childrens Med Res Ctr, Div Res Promot, Setagaya Ku, Tokyo 1548509, Japan
[2] Sci Univ Tokyo, Fac Sci & Technol, Dept Appl Biol Sci, Noda, Chiba 2788510, Japan
[3] Showa Univ, Sch Pharmaceut Sci, Lab Biopharmaceut, Shinagawa Ku, Tokyo 1428555, Japan
来源
JAPANESE JOURNAL OF CANCER RESEARCH | 2001年 / 92卷 / 06期
关键词
FTY720; cell cycle arrest; apoptosis; retinoblastoma protein; lymphoma cells;
D O I
10.1111/j.1349-7006.2001.tb01148.x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
A novel reagent, FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrorhloride), has been shown to induce a significant decrease of lymphocytes and lymphoma cells and is expected to be a potent immunosuppressant and anti-tumor drug. The decrease in lymphocytes and lymphoma cells is mainly the result of FTY720-indured apoptosis, FTY720 directly affects mitochondria and induces cell death. Moreover, FTY720 activates protein phosphatase IPP) 2A and affects anti-apoptotic intracellular signal transduction proteins to attenuate the anti-apoptotic effect. III this study, we examined the relationship between FTY720-induced apoptosis and cell cycle regulation. FTY720 induced apoptosis significantly at the G0/G1 phase and caused G0/G1 cell cycle arrest of the human lymphoma cell lines HL-60RG and Jurkat, Simultaneously, retinoblastoma protein (pRB) was dephosphorylated, suggesting that dephosphorylation of pRB was related to FTY720-inductd G0/G1 cell cycle arrest. Because this dephosphorylation was completely blocked by a specific PP1/2A inhibitor, okadaic acid, it appears that FTY720-artivated PP2A is essential for FTY720-induccd cell cycle arrest. FTY720-induced apoptosis was inhibited by Bcl-2 overexpression in Jurkat cells, but this did not prevent FTY720-induced cell cycle arrest, suggesting that the mechanism of FTY720-induced cell cycle arrest is independent of the mechanism of FTY720-induced apoptosis, These two independent pathways strengthen the effect of FTY720.
引用
收藏
页码:680 / 687
页数:8
相关论文
共 39 条
[1]   REGULATION OF CELL-CYCLE PROGRESSION AND NUCLEAR AFFINITY OF THE RETINOBLASTOMA PROTEIN BY PROTEIN PHOSPHATASES [J].
ALBERTS, AS ;
THORBURN, AM ;
SHENOLIKAR, S ;
MUMBY, MC ;
FERAMISCO, JR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (02) :388-392
[2]   THE RETINOBLASTOMA PROTEIN IS PHOSPHORYLATED DURING SPECIFIC PHASES OF THE CELL-CYCLE [J].
BUCHKOVICH, K ;
DUFFY, LA ;
HARLOW, E .
CELL, 1989, 58 (06) :1097-1105
[3]   PROTEIN-KINASE-B (C-AKT) IN PHOSPHATIDYLINOSITOL-3-OH INASE SIGNAL-TRANSDUCTION [J].
BURGERING, BMT ;
COFFER, PJ .
NATURE, 1995, 376 (6541) :599-602
[4]   PHOSPHORYLATION OF THE RETINOBLASTOMA GENE-PRODUCT IS MODULATED DURING THE CELL-CYCLE AND CELLULAR-DIFFERENTIATION [J].
CHEN, PL ;
SCULLY, P ;
SHEW, JY ;
WANG, JYJ ;
LEE, WH .
CELL, 1989, 58 (06) :1193-1198
[5]   Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation [J].
ConnellCrowley, L ;
Harper, JW ;
Goodrich, DW .
MOLECULAR BIOLOGY OF THE CELL, 1997, 8 (02) :287-301
[6]   INDUCTION OF A RETINOBLASTOMA PHOSPHATASE-ACTIVITY BY ANTICANCER DRUGS ACCOMPANIES P53-INDEPENDENT G(1) ARREST AND APOPTOSIS [J].
DOU, QP ;
AN, B ;
WILL, PL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (20) :9019-9023
[7]   DIFFERENTIAL REGULATION OF E2F TRANSACTIVATION BY CYCLIN CDK2 COMPLEXES [J].
DYNLACHT, BD ;
FLORES, O ;
LEES, JA ;
HARLOW, E .
GENES & DEVELOPMENT, 1994, 8 (15) :1772-1786
[8]   Cell cycle regulation of p70 S6 kinase and p42/p44 mitogen-activated protein kinases in Swiss mouse 3T3 fibroblasts [J].
Edelmann, HML ;
Kuhne, C ;
Petritsch, C ;
Ballou, LM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (02) :963-971
[9]  
ELDEIRY WS, 1994, CANCER RES, V54, P1169
[10]   Induction of selective cell death targeting on mature T-lymphocytes in rats by a novel immunosuppressant, FTY720 [J].
Enosawa, S ;
Suzuki, S ;
Kakefuda, T ;
Li, XK ;
Amemiya, H .
IMMUNOPHARMACOLOGY, 1996, 34 (2-3) :171-179