期刊
CANCER RESEARCH
卷 65, 期 16, 页码 7338-7347出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-04-2263
关键词
-
类别
资金
- NCI NIH HHS [2PO1CA66996-06] Funding Source: Medline
Internal tandem duplication (ITD) mutations in the FLT3 tyrosine kinase have been detected in similar to 20% of acute myeloid leukemia (AML) patients. Patients harboring FLT3/ITD mutations have a relatively poor prognosis. FLT3/ITD results in constitutive autophosphorylation of the receptor and factor-independent survival. Previous studies have shown that FLT3/ITD activates the signal transducers and activators of transcription 5 (STAT5), p42/p44 mitogen-activated protein kinase [MAPK; extracellular signal-regulated kinase (ERK) 1/2], and phosphatidylinositol 3-kinase/Akt pathways. We herein provide biochemical and biological evidence that ribosomal S6 kinase I (RSK1) and protein kinase A (PKA) are the two principal kinases that mediate the antiapoptotic function of FLT3/ITD via phosphorylation of BAD at Ser(112). Inhibiting both MAPK kinase (MEK)/ERK and PKA pathways by a combination of U0126 (10 mu mol/L) and H-89 (5 mu mol/L) reduced most of BAD phosphorylation at Ser(112) and induced apoptosis to a level comparable with that induced by FLT3 inhibitor AG1296 (5 mu mol/L) in BaF3/FLT3/ITD cells. RNA interference of RSK1 or PKA catalytic subunit reduced BAD phosphorylation and induced apoptosis. The MEK inhibitor U0126 and/or the PKA inhibitor H-89 greatly enhanced the efficacy of the FLT3 inhibitor AG1296, suggesting that combining FLT3/ITD downstream pathway inhibition with FLT3 inhibitors may be a viable therapeutic strategy for AML caused by a FLT3/ITD mutation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据