Bacterial N-acylhomoserine lactone-induced apoptosis in breast carcinoma cells correlated with down-modulation of STAT3
Bacterial N-acylhomoserine lactone-induced apoptosis in breast carcinoma cells correlated with down-modulation of STAT3
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DOI：
10.1038/sj.onc.1207612
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发表时间：
2004-06-17
期刊：
影响因子：
8
通讯作者：
Shaw, PE
中科院分区：
文献类型：
--
作者：
Li, L;Hooi, D;Shaw, PE
细胞生长是由分裂原和存活因子促进的，它们激活细胞内信号通路来控制细胞周期进程和细胞完整性。增殖信号通过Ras和Rho家族小g蛋白偶联至丝裂原活化蛋白激酶（MAPK）级联传递，而存活信号则通过脂质依赖性激酶如磷脂酰亚脂3激酶（pi3k）和蛋白激酶B （Akt/PKB）传播。近年来，信号换能器和转录激活因子（STAT）蛋白在多种细胞类型中被鉴定为增殖的正调控因子。这些通路的持续激活与肿瘤细胞生长有关，而抑制它们可以阻止增殖并导致凋亡细胞死亡。人类病原体铜绿假单胞菌利用群体感应信号分子（QSSMs）调控毒力基因表达。QSSMs也抑制宿主免疫应答，但抑制机制尚不清楚。在这里，我们证明了来自P. aeruginosa的QSSM N-（3-氧十二烷基）- l -高丝氨酸内酯（OdDHL）可抑制人BC细胞系的增殖并诱导凋亡。对信号事件的分析表明，OdDHL对MAPK级联的影响很小或没有影响，部分抑制Akt/PKB通路并降低STAT3活性。每种途径的药理学抑制独立表明STAT3活性对BC细胞增殖和存活至关重要，而组成性活性STAT3赋予对OdDHL的抗性。这些结果支持OdDHL作为真核生物系统中的生物活性分子的概念，并为一类新型抗增殖化合物提供了范例。
Cell growth is promoted by mitogens and survival factors, which activate intracellular signalling pathways to control cell cycle progression and cellular integrity. Proliferation signals are transmitted through Ras and Rho family small G-proteins coupled to mitogen-activated protein kinase ( MAPK) cascades, while survival signals are propagated by lipid-dependent kinases such as phosphatidylinositide 3-kinases (PI3Ks) and protein kinase B (Akt/PKB). Recently, signal transducer and activator of transcription ( STAT) proteins were identified as positive regulators of proliferation in a variety of cell types. Persistent activation of these pathways is associated with tumour cell growth, whereas their inhibition can halt proliferation and precipitate apoptotic cell death. The human pathogen Pseudomonas aeruginosa uses quorum-sensing signal molecules (QSSMs) to regulate virulence gene expression. QSSMs also suppress host immune responses although the mechanism of suppression is unknown. Here, we demonstrate that the QSSM N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) from P. aeruginosa blocks proliferation and induces apoptosis in human BC cell lines. Analyses of signalling events reveal that OdDHL has little or no effect on MAPK cascades, partially inhibits the Akt/PKB pathway and ablates STAT3 activity. Pharmacological inhibition of each pathway independently indicates that STAT3 activity is critical for BC cell proliferation and survival, while a constitutively active STAT3 confers resistance to OdDHL. These results support the notion of OdDHL as a bioactive molecule in eukaryotic systems and a paradigm for a novel class of antiproliferative compounds.