Selective inhibition of STAT3 induces apoptosis and G1 cell cycle arrest in ALK-positive anaplastic large cell lymphoma
Selective inhibition of STAT3 induces apoptosis and G1 cell cycle arrest in ALK-positive anaplastic large cell lymphoma
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DOI：
10.1038/sj.onc.1207703
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发表时间：
2004-07-15
期刊：
影响因子：
8
通讯作者：
Lai, R
中科院分区：
文献类型：
--
作者：
Amin, HM;McDonnell, TJ;Lai, R
核磷蛋白-间变性淋巴瘤激酶 (NPM-ALK) 是一种异常融合基因产物，在部分间变性大细胞淋巴瘤 (ALCL) 病例中表达。研究表明，NPM-ALK 在体外结合并激活信号转导子和转录激活子 3 (STAT3)，并且 STAT3 在 ALK(+) ALCL 细胞系和肿瘤中具有持续活性。鉴于 STAT3 的致癌潜力，我们使用两种 ALK(+) ALCL 细胞系（Karpas 299 和 SU-DHL-1）和携带显性失活 STAT3 的腺病毒载体 (AdSTAT3DN) 进一步研究了其在 ALCL 中的生物学意义。 AdSTAT3DN 感染导致 STAT3DN 在两种 ALK(+) ALCL 细胞系中以相似的效率表达。亚细胞分级分离研究表明，尽管 STAT3DN 在残基 705（酪氨酸 --> 苯丙氨酸）处存在突变，但表达的 STAT3DN 蛋白的很大一部分易位至细胞核，该位点被认为对于 STAT3 激活和核易位至关重要。 STAT3DN 的引入诱导细胞凋亡和 G，细胞周期停滞。蛋白质印迹研究表明，STAT3DN 的表达导致 caspase-3 裂解，Bcl-2、Bcl-xL、细胞周期蛋白 D3、生存素、Mcl-1、c-Myc 和细胞因子信号传导抑制因子 3 的下调。这些结果支持这样的观点，即 STAT3 激活通过解除对参与细胞凋亡和细胞周期进程控制的多个靶蛋白的表达的调节，在 ALCL 细胞中具有重要的发病机制。
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is an aberrant fusion gene product expressed in a subset of cases of anaplastic large cell lymphoma (ALCL). It has been shown that NPM-ALK binds to and activates signal transducer and activator of transcription 3 (STAT3) in vitro, and that STAT3 is constitutively active in ALK(+) ALCL cell lines and tumors. In view of the oncogenic potential of STAT3, we further examined its biological significance in ALCL using two ALK(+) ALCL cell lines (Karpas 299 and SU-DHL-1) and an adenoviral vector that carries dominant-negative STAT3 (AdSTAT3DN). Infection by AdSTAT3DN led to the expression of STAT3DN in both ALK(+) ALCL cell lines at a similar efficiency. Subcellular fractionation studies showed that a significant proportion of the expressed STAT3DN protein translocated to the nucleus, despite the fact that STAT3DN has a mutation at residue 705(tyrosine --> phenylalanine), a site that is believed to be crucial for STAT3 activation and nuclear translocation. Introduction of STAT3DN induced apoptosis and G, cell cycle arrest. Western blot studies showed that expression of STAT3DN resulted in caspase-3 cleavage, downregulation of Bcl-2, Bcl-xL, cyclin D3, survivin, Mcl-1, c-Myc and suppressor of cytokine signaling 3. These results support the concept that STAT3 activation is pathogenetically important in ALCL cells by deregulating the expression of multiple target proteins that are involved in the control of apoptosis and cell cycle progression.