Differential effects of Stat3 inhibition in sparse vs confluent normal and breast cancer cells
Differential effects of Stat3 inhibition in sparse vs confluent normal and breast cancer cells
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DOI：
10.1016/j.canlet.2005.10.047
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发表时间：
2006-10-08
期刊：
影响因子：
9.7
通讯作者：
Raptis, Leda
中科院分区：
文献类型：
--
作者：
Anagnostopouloua, Aikaterini;Vultur, Adina;Raptis, Leda
信号转导子和转录激活子-3（Stat 3）在许多癌症如乳腺癌中持续激活，并且是许多癌基因转化所必需的。通过Stat 3的信号传导由tyr-705处的关键磷酸化决定。我们先前证明，通过培养细胞的细胞聚集或汇合引起的细胞与细胞粘附导致Stat 3 tyr 705磷酸化的显著增加，从而导致正常细胞和肿瘤细胞中Stat 3活性的显著增加。为了检查Stat 3在相对于汇合的特定时间点的作用，我们使用了两种不同的Stat 3抑制方法：（1）。引入高水平的肽类似物，其阻断Stat 3-SH 2结构域，以抑制Stat 3与生长因子受体的结合和磷酸化。（二）、用结合Stat 3蛋白并抑制其活性而不直接影响其磷酸化的两种铂化合物处理。结果表明，Stat 3下调vSrc转化的NIH 3 T3细胞或乳腺癌细胞系携带激活的Src诱导细胞凋亡，这是明显的，在所有密度，但在汇合后更明显。另一方面，在正常细胞中，在汇合后抑制Stat 3引起细胞凋亡，而在稀疏生长的细胞中，它仅诱导生长迟缓。(c)2005爱思唯尔爱尔兰有限公司保留所有权利。
The signal transducer and activator of transcription-3 (Stat3) is persistently activated in many cancers such as cancer of the breast and is required for transformation by a number of oncogenes. Signaling through Stat3 is determined by a key phosphorylation at tyr-705. We previously demonstrated that cell-to-cell adhesion brought about through cell aggregation or confluence of cultured cells causes a dramatic increase in Stat3 tyr705 phosphorylation and consequently Stat3 activity in both normal and tumor cells. To examine the role of Stat3 at specific time-points relative to confluence, we used two different approaches of Stat3 inhibition: (1). Introduction of high levels of peptide analogues, which block the Stat3-SH2 domain, to inhibit Stat3 binding to and phosphorylation by growth factor receptors. (2). Treatment with two platinum compounds which bind the Stat3 protein and inhibit its activity without affecting its phosphorylation directly. The results demonstrate that Stat3 downregulation in vSrc transformed NIH3T3 cells or in breast cancer lines harboring activated Src induces apoptosis, which is evident at all densities but is more pronounced at post-confluence. In normal cells on the other hand, Stat3 inhibition at post-confluence caused apoptosis while in sparsely growing cells it induced merely a growth retardation. (c) 2005 Elsevier Ireland Ltd. All rights reserved.