Spred2 is involved in imatinib-induced cytotoxicity in chronic myeloid leukemia cells
Spred2 is involved in imatinib-induced cytotoxicity in chronic myeloid leukemia cells
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Spred2参与伊马替尼诱导的慢性粒细胞白血病细胞毒性
DOI：
10.1016/j.bbrc.2010.02.044
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发表时间：
2010-03-19
影响因子：
3.1
通讯作者：
Wang, Li-Sheng
中科院分区：
文献类型：
--
作者：
Liu, Xiao-Yun;Yang, Yue-Feng;Wang, Li-Sheng
Spreds是最近发现的Ras-ERK（细胞外信号调节激酶）通路的一类负调节因子，参与血液生成、过敏性疾病和肿瘤发生。然而，它们在血液肿瘤中的作用在很大程度上是未知的。Spreds对与Ras-ERK密切相关的其他信号通路的可能影响的研究很少。在这项研究中，我们研究了Spred2对慢性髓性白血病（CML）细胞的体外作用。除了抑制Ras-ERK级联外，腺病毒介导的Spred2过表达还抑制构成型和干细胞因子（SCF）刺激的鞘氨酸激酶-1 （SPHK1）和Mcl-1的表达，以及抑制CML细胞的增殖和诱导凋亡。在K562细胞和原代CML细胞中，伊马替尼诱导内源性Spred2表达。通过稳定的RNA干扰使Spred2沉默部分保护K562细胞免受伊马替尼诱导的凋亡。综上所述，这些数据暗示Spred2可能通过抑制Ras-ERK级联和促生存信号分子SPHK1和Mcl-1参与伊马替尼诱导的CML细胞毒性。这些发现揭示了CML选择性治疗的潜在靶点。(C) 2010爱思唯尔公司版权所有。
Spreds, a recently established class of negative regulators of the Ras-ERK (extracellular signal-regulated kinase) pathway, are involved in hematogenesises, allergic disorders and tumourigenesis. However, their role in hematologic neoplasms is largely unknown. Possible effects of Spreds on other signal pathways closely related to Ras-ERK have been poorly investigated. In this study, we investigated the in vitro effects of Spred2 on chronic myeloid leukemia (CML) cells. In addition to inhibiting the well-established Ras-ERK cascade, adenovirus-mediated Spred2 over-expression inhibits constitutive and stem cell factor (SCF)-stimulated sphingosine kinase-1 (SPHK1) and Mcl-1 expression, as well as inhibiting proliferation and inducing apoptosis in CML cells. In K562 cells and primary CML cells, imatinib induces endogenous Spred2 expression. Spred2 silencing by stable RNA interference partly protects K562 cells against imatinib-induced apoptosis. Together, these data implicate Spred2 in imatinib-induced cytotoxicity in CML cells, possibly by inhibiting the Ras-ERK cascade and the pro-survival signaling molecules SPHK1 and Mcl-1. These findings reveal potential targets for selective therapy of CML. (C) 2010 Elsevier Inc. All rights reserved.