Src kinase family inhibitor PP2 induces aggregation and detachment of neuroblastoma cells and inhibits cell growth in a PI3 kinase/Akt pathway-independent manner
Src kinase family inhibitor PP2 induces aggregation and detachment of neuroblastoma cells and inhibits cell growth in a PI3 kinase/Akt pathway-independent manner
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DOI：
10.1007/s00383-010-2775-2
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发表时间：
2011-02-01
影响因子：
1.8
通讯作者：
Yoshida, Hideo
中科院分区：
文献类型：
--
作者：
Hishiki, Tomoro;Saito, Takeshi;Yoshida, Hideo
神经母细胞瘤（NB）是儿童最常见的颅外实体瘤之一，其临床和生物学异质性众所周知。本研究的目的是通过用特异性抑制剂PP 2抑制src家族激酶的活性，揭示src家族激酶在NB生物学行为中的功能作用（4-氨基-5-（4-氯-苯基）-7-（叔丁基）吡唑并[3，4-d]嘧啶）.NB细胞系用0.1-10 μ M的PP 2处理（SH-SY 5 Y、IMR 32、RT-BM-1、CHP 134、NLF和LA-N-5）。形态学变化，细胞生长，细胞死亡进行了评估，以及全反式维甲酸（ATRA）诱导的神经元分化和表皮生长因子（EGF）诱导的proliferation.At 24 h后PP 2处理，NB细胞系显示激烈的细胞聚集。PP 2也以剂量依赖性方式抑制NB细胞的生长。在这些细胞中检测到凋亡。ATRA诱导的RT-BM-1的神经元分化不受PP 2的影响。PP 2可降低EGF的促增殖作用。EGF可诱导Akt的快速激活，PP 2不能阻断这种激活，提示PP 2所触发的细胞事件不依赖于PI 3激酶/Akt信号通路，src家族激酶可促进细胞存活/增殖，减少NB的细胞聚集。Src家族激酶抑制剂可能是一种新型分子靶向治疗的良好候选药物。
Neuroblastoma (NB) is one of the most common extracranial solid tumors in children and is known for its clinical and biological heterogeneity. The aim of this study is to reveal the functional role of src family kinases in the biological behavior of NB by inhibiting their kinase activities with a specific inhibitor, PP2 (4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine).NB cell lines (SH-SY5Y, IMR32, RT-BM-1, CHP134, NLF, and LA-N-5) were treated with 0.1-10 A mu M of PP2. Morphological changes, cell growth, and cell death were assessed, as well as all-trans retinoic acid (ATRA)-induced neuronal differentiation and epidermal growth factor (EGF)-induced proliferation.At 24 h after PP2 treatment, NB cell lines showed drastic cell aggregation. PP2 also inhibited cell growth of NB in a dose-dependent manner. Apoptosis was detected in these cells. ATRA-induced neuronal differentiation of RT-BM-1 was not affected by PP2. PP2 reduced the proliferative effect of EGF. EGF-induced rapid activation of Akt, which was not blocked by PP2 treatment, suggesting that the cellular events triggered by PP2 were independent to PI3 kinase/Akt signaling pathway.Our data suggests that src family kinases promote cell survival/proliferation and reduces cell aggregation of NBs. Src family kinase inhibitors may be good candidates for a novel molecular target therapy.