Src family kinases promote AML cell survival through activation of signal transducers and activators of transcription (STAT)

被引：49
作者：
Ozawa, Yukiyasu [1 ]
Williams, Ann H. [1 ]
Estes, Myka L. [1 ]
Matsushita, Norimasa [2 ]
Boschelli, Frank [3 ]
Jove, Richard [1 ]
List, Alan F. [1 ]
机构：
[1] H Lee Moffitt Canc & Res Inst, Tampa, FL 33612 USA
[2] H Lee Moffitt Canc & Res Inst, Program Immunol, Tampa, FL 33612 USA
[3] Wyeth Res, Dept Oncol, Pearl River, NY USA
来源：
LEUKEMIA RESEARCH | 2008年 / 32卷 / 06期
关键词：
Src family kinase; STAT5; Akt;
D O I：
10.1016/j.leukres.2007.11.032
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
We investigated the role of Src family kinases (SFKs) in the regulation of STAT activation in myeloid leukemia cells. Two of 6 AML cell lines displayed constitutive STAT5 activation, whereas four cell lines had constitutive SFK activity. Treatment with the SFK inhibitors suppressed STAT5 activation and decreased viability. Akt phosphorylation and Mcl-1 expression decreased after SFK inhibition accompanied by apoptosis induction. In primary AML specimens, SFK inhibitors suppressed proliferation in 5 of 14 specimens. These data indicate that Src-STAT5 and Src-Akt pathways are integral survival signal pathways in AML cells. Src inhibition may represent a novel treatment strategy for investigation in AML. (c) 2007 Elsevier Ltd. All rights reserved.
引用
收藏
页码：893 / 903
页数：11
相关论文
共 52 条
[1]   Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival [J].
Benekli, M ;
Xia, Z ;
Donohue, KA ;
Ford, LA ;
Pixley, LA ;
Baer, MR ;
Baumann, H ;
Wetzler, M .
BLOOD, 2002, 99 (01) :252-257
[2]   Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity [J].
Boschelli, DH ;
Ye, F ;
Wang, YD ;
Dutia, M ;
Johnson, SL ;
Wu, BQ ;
Miller, K ;
Powell, DW ;
Yaczko, D ;
Young, M ;
Tischler, M ;
Arndt, K ;
Discafani, C ;
Etienne, C ;
Gibbons, J ;
Grod, J ;
Lucas, J ;
Weber, JM ;
Boschelli, F .
JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (23) :3965-3977
[3]   STATs in oncogenesis [J].
Bowman, T ;
Garcia, R ;
Turkson, J ;
Jove, R .
ONCOGENE, 2000, 19 (21) :2474-2488
[4]   The role of STATs in transcriptional control and their impact on cellular function [J].
Bromberg, J ;
Darnell, JE .
ONCOGENE, 2000, 19 (21) :2468-2473
[5]   Stat3 activation is required for cellular transformation by v-src [J].
Bromberg, JF ;
Horvath, CM ;
Besser, D ;
Lathem, WW ;
Darnell, JE .
MOLECULAR AND CELLULAR BIOLOGY, 1998, 18 (05) :2553-2558
[6]   Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl [J].
Carlesso, N ;
Frank, DA ;
Griffin, JD .
JOURNAL OF EXPERIMENTAL MEDICINE, 1996, 183 (03) :811-820
[7]   PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells [J].
Castoria, G ;
Migliaccio, A ;
Bilancio, A ;
Di Domenico, M ;
de Falco, A ;
Lombardi, M ;
Fiorentino, R ;
Varricchio, L ;
Barone, MV ;
Auricchio, F .
EMBO JOURNAL, 2001, 20 (21) :6050-6059
[8]   Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells [J].
Catlett-Falcone, R ;
Landowski, TH ;
Oshiro, MM ;
Turkson, J ;
Levitzki, A ;
Savino, R ;
Ciliberto, G ;
Moscinski, L ;
Fernández-Luna, JL ;
Nuñez, G ;
Dalton, WS ;
Jove, R .
IMMUNITY, 1999, 10 (01) :105-115
[9]   Src kinases and not JAKs activate STATs during IL-3 induced myeloid cell proliferation [J].
Chaturvedi, P ;
Reddy, MVR ;
Reddy, EP .
ONCOGENE, 1998, 16 (13) :1749-1758
[10]   Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970 [J].
Corbin, AS ;
Griswold, IJ ;
La Rosée, P ;
Yee, KWH ;
Heinrich, MC ;
Reimer, CL ;
Druker, BJ ;
Deininger, MWN .
BLOOD, 2004, 104 (12) :3754-3757
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