A novel phosphatidylinositol 3-kinase (PI3K) inhibitor directs a potent FOXO-dependent, p53-independent cell cycle arrest phenotype characterized by the differential induction of a subset of FOXO-regulated genes.
A novel phosphatidylinositol 3-kinase (PI3K) inhibitor directs a potent FOXO-dependent, p53-independent cell cycle arrest phenotype characterized by the differential induction of a subset of FOXO-regulated genes.
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DOI：
10.1186/s13058-014-0482-y
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发表时间：
2014-12-09
期刊：
影响因子：
--
通讯作者：
Link W
中科院分区：
文献类型：
--
作者：
Hill R;Kalathur RK;Callejas S;Colaço L;Brandão R;Serelde B;Cebriá A;Blanco-Aparicio C;Pastor J;Futschik M;Dopazo A;Link W
磷酸肌醇3-激酶(PI3K)/AKT信号通路的激活是乳腺癌中最常见的遗传事件之一，因此开发PI3K抑制剂备受关注。在这里，我们评估了PI3K抑制对乳腺癌细胞中全局基因表达的影响。我们使用了一系列的方法，包括硅化合物分析，体外激酶测定，细胞侵袭测定，增殖测定，全基因组转录研究（Agilent Technologies全基因组阵列），基因集富集分析，定量实时PCR，除染色质免疫沉淀外的免疫印迹。我们确定了一种新型有效的PI3K抑制剂ETP-45658的物理化学和生物学特性。我们证明了ETP-45658在广泛的人类癌细胞中有效地抑制细胞增殖，其中最有效的是通过抑制细胞周期来抑制乳腺癌细胞的生长。我们发现这种反应依赖于叉头盒O （FOXO）蛋白，而不依赖于p53。我们的全基因组微阵列分析显示，暴露于ETP-45658（或我们的对照PI3K抑制剂PI-103）后，细胞周期是受影响最大的生物过程，尽管PI3K/AKT信号级联调节多种转录因子，但只有FOXO转录因子的结合位点显著富集，并且只有一部分FOXO依赖基因被诱导。这种基因转录的差异不是由于FOXO启动子募集的差异。pi3k的组成性激活和FOXO转录因子从细胞核中被排除是乳腺癌的一个关键特征。我们的研究结果强调，PI3K抑制激活了介导乳腺癌细胞周期阻滞的foxo特异性依赖基因。本文的在线版本（doi:10.1186/s13058-014-0482-y）包含补充材料，可供授权用户使用。
The activation of the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is one the most frequent genetic events in breast cancer, consequently the development of PI3K inhibitors has attracted much attention. Here we evaluate the effect of PI3K inhibition on global gene expression in breast cancer cells. We used a range of methodologies that include in silico compound analysis, in vitro kinase assays, cell invasion assays, proliferation assays, genome-wide transcription studies (Agilent Technologies full genome arrays), gene set enrichment analysis, quantitative real-time PCR, immunoblotting in addition to chromatin immunoprecipitation. We defined the physico-chemical and the biological properties of ETP-45658, a novel potent PI3K inhibitor. We demonstrated that ETP-45658 potently inhibited cell proliferation within a broad range of human cancer cells, most potently suppressing the growth of breast cancer cells via inhibiting cell cycle. We show that this response is Forkhead box O (FOXO) protein dependent and p53 independent. Our genome-wide microarray analysis revealed that the cell cycle was the most affected biological process after exposure to ETP-45658 (or our control PI3K inhibitor PI-103), that despite the multiple transcription factors that are regulated by the PI3K/AKT signalling cascade, only the binding sites for FOXO transcription factors were significantly enriched and only a subset of all FOXO-dependent genes were induced. This disparity in gene transcription was not due to differential FOXO promoter recruitment. The constitutive activation of PI3Ks and thus the exclusion of FOXO transcription factors from the nucleus is a key feature of breast cancer. Our results presented here highlight that PI3K inhibition activates specific FOXO-dependent genes that mediate cell cycle arrest in breast cancer cells. The online version of this article (doi:10.1186/s13058-014-0482-y) contains supplementary material, which is available to authorized users.
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DOI：
10.1083/jcb.200403069
发表时间：
2004-07-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harrington LS;Findlay GM;Gray A;Tolkacheva T;Wigfield S;Rebholz H;Barnett J;Leslie NR;Cheng S;Shepherd PR;Gout I;Downes CP;Lamb RF
通讯作者：
Lamb RF
影响因子：
9.9
作者：
Eijkelenboom, Astrid;Mokry, Michal;Burgering, Boudewijn M. T.
通讯作者：
Burgering, Boudewijn M. T.
DOI：
10.1093/jnci/djr350
发表时间：
2011-10-01
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Baranwal, Somesh;Wang, Yanfang;Alahari, Suresh K.
通讯作者：
Alahari, Suresh K.
影响因子：
3.6
作者：
Bachman, KE;Argani, P;Park, BH
通讯作者：
Park, BH
影响因子：
4.3
作者：
Guillard, Sandrine;Clarke, Paul A.;Workman, Paul
通讯作者：
Workman, Paul