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
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
[11]   Src-related protein tyrosine kinases in hematopoiesis [J].
Corey, SJ ;
Anderson, SM .
BLOOD, 1999, 93 (01) :1-14
[12]   JAK-STAT PATHWAYS AND TRANSCRIPTIONAL ACTIVATION IN RESPONSE TO IFNS AND OTHER EXTRACELLULAR SIGNALING PROTEINS [J].
DARNELL, JE ;
KERR, IM ;
STARK, GR .
SCIENCE, 1994, 264 (5164) :1415-1421
[13]   STAT5 activation by BCR-Abl contributes to transformation of K562 leukemia cells [J].
de Groot, RP ;
Raaijmakers, JAM ;
Lammers, JWJ ;
Jove, R ;
Koenderman, L .
BLOOD, 1999, 94 (03) :1108-1112
[14]   Prolactin induces c-Myc expression and cell survival through activation of Src/Akt pathway in lymphoid cells [J].
Domínguez-Cáceres, MA ;
García-Martínez, JM ;
Calcabrini, A ;
González, L ;
Porque, PG ;
León, J ;
Martín-Pérez, J .
ONCOGENE, 2004, 23 (44) :7378-7390
[15]  
Dorsey JF, 2000, CANCER RES, V60, P3127
[16]   Carboxy-terminal truncated STAT5 is induced by interleukin-2 and GM-CSF in human neutrophils [J].
Epling-Burnette, PK ;
Garcia, R ;
Bai, FQ ;
Ismail, S ;
Loughran, TP ;
Djeu, JY ;
Jove, R ;
Wei, S .
CELLULAR IMMUNOLOGY, 2002, 217 (1-2) :1-11
[17]   B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT)1 and STAT3 constitutively phosphorylated on serine residues [J].
Frank, DA ;
Mahajan, S ;
Ritz, J .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (12) :3140-3148
[18]   Role of FLT3 in leukemia [J].
Gilliland, DG ;
Griffin, JD .
CURRENT OPINION IN HEMATOLOGY, 2002, 9 (04) :274-281
[19]  
Golas JM, 2003, CANCER RES, V63, P375
[20]   SKI-606, a Src/AbI inhibitor with in vivo activity in colon tumor xenograft models [J].
Golas, JM ;
Lucas, J ;
Etienne, C ;
Golas, J ;
Discafani, C ;
Sridharan, L ;
Boghaert, E ;
Arndt, K ;
Ye, F ;
Boschelli, DH ;
Li, FB ;
Titsch, C ;
Huselton, C ;
Chaudhary, I ;
Boschelli, F .
CANCER RESEARCH, 2005, 65 (12) :5358-5364