Insulin Receptor (IR) Pathway Hyperactivity in IGF-IR Null Cells and Suppression of Downstream Growth Signaling Using the Dual IGF-IR/IR Inhibitor, BMS-754807
Insulin Receptor (IR) Pathway Hyperactivity in IGF-IR Null Cells and Suppression of Downstream Growth Signaling Using the Dual IGF-IR/IR Inhibitor, BMS-754807
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DOI：
10.1210/en.2010-0032
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发表时间：
2010-09-01
期刊：
影响因子：
4.8
通讯作者：
Carboni, Joan M.
中科院分区：
文献类型：
--
作者：
Dinchuk, Joseph E.;Cao, Carolyn;Carboni, Joan M.
在正常小鼠胚胎成纤维细胞（mef）中研究了IGF-IR/IR信号的生物学特性，这些细胞分别为野生型（wt）、杂合型（het）或IGF-IR为零。IGF-I、IGF-II或胰岛素刺激血清饥饿mef的能力通过基因表达谱和下游信号激活的生化分析来表征。每个基因型组的mef在静息和刺激反应时都表现出不同的表达模式。胰岛素受体（IR）通路在IGF-IR无效mef中对胰岛素配体刺激敏感，导致AKT磷酸化程度高于受相同配体刺激的wt或ht mef。有趣的是，在IGF-IR无效mef中，IR通路的超敏反应发生时，IR异构体A或b的水平没有观察到变化。一种新的小分子IGF-IR抑制剂（BMS-754807）对IGF-IR和IR具有同等的活性，在wt、ht和无效mef中测试的所有三种配体都有效地抑制了IGF-IR和IR通路上AKT和ERK的磷酸化。双重IGF-IR/IR抑制剂的使用解决了在某些癌症中使用针对IGF-IR受体的生长抑制疗法的问题。最后，对各种化合物在wt和无效mef中的抗增殖作用（IC(50)s）的比较表明，具有遗传特征的mef提供了一种简单而廉价的工具，用于定义化合物主要具有靶向或脱靶的IGF-IR活性，因为脱靶化合物对wt和无效mef的影响是相同的。（中国医学杂志，2010）
The biology of IGF-IR/IR signaling was studied in normal mouse embryonic fibroblasts (MEFs) that were either wild type (wt), heterozygous (het), or null for the IGF-IR. The ability of IGF-I, IGF-II, or insulin to stimulate serum-starved MEFs was characterized by gene expression profiling and biochemical analyses for activation of downstream signals. Each genotypic group of MEFs exhibited distinct patterns of expression both while resting and in response to stimulation. The insulin receptor (IR) pathway in IGF-IR null MEFs was hypersensitive to insulin ligand stimulation resulting in greater AKT phosphorylation than in wt or het MEFs stimulated with the same ligand. Interestingly, the IR pathway hypersensitivity in IGF-IR null MEFs occurred with no observed changes in the levels of IR isoforms A or B. A new small molecule IGF-IR inhibitor (BMS-754807), having equipotent activity against both IGF-IR and IR, proved effective in suppressing both AKT and ERK phosphorylation from both the IGF-IR and IR pathways by all three ligands tested in wt, het, and null MEFs. The use of a dual IGF-IR/IR inhibitor addresses concerns about the use of growth inhibiting therapies directed against the IGF-IR receptor in certain cancers. Lastly, comparison of the antiproliferative effects (IC(50)s) of various compounds in wt vs. null MEFs demonstrates that genetically characterized MEFs provide a simple and inexpensive tool with which to define compounds as having mostly on-target or off-target IGF-IR activities because off-target compounds affect both wt and null MEFs equally. (Endocrinology 151: 4123-4132, 2010)