Activation of the insulin-like growth factor 1 signaling pathway by the antiapoptotic agents aurintricarboxylic acid and Evans blue
Activation of the insulin-like growth factor 1 signaling pathway by the antiapoptotic agents aurintricarboxylic acid and Evans blue
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DOI：
10.1210/en.142.7.3098
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发表时间：
2001-07-01
期刊：
影响因子：
4.8
通讯作者：
Geier, A
中科院分区：
文献类型：
--
作者：
Beery, R;Haimsohn, M;Geier, A
金精三羧酸（ATA）是一种核酸内切酶抑制剂，可防止培养中多种细胞类型的死亡。以前，我们已经表明，ATA，类似于胰岛素样生长因子I（IGF-I），保护MCF-7细胞对蛋白质合成抑制剂放线菌酮诱导的凋亡死亡。在这里，我们表明，ATA和多磺化芳香族化合物，伊文思蓝（EB），类似于IGF-I，促进MCF-7细胞在无血清培养基中的存活和增殖。这可能表明芳香族聚阴离子和IGF-I共享的共同信号传导途径。因此，检测了这些芳香族化合物激活IGF-I的信号转导途径的能力。我们发现ATA和EB模拟IGF-I对IGF-I受体（IGF-IR）及其主要底物胰岛素受体底物-1（IRS-1）和IRS-P酪氨酸磷酸化的作用：诱导这些底物与磷脂酰肌醇3-激酶和Grb 2的结合;并激活Akt激酶和p42/p44丝裂原活化蛋白激酶。ATA和EB竞争IGF-I与IGF-IR的结合，ATA对IGF-IR具有选择性，而EB也激活胰岛素受体。在通过尺寸排阻色谱法分离商业ATA后，我们发现，增强酪氨酰磷酸化IRS-1/IRS-2强度的组分也增加了放线菌酮存在下MCF-7细胞的存活率，而缺乏IRS磷酸化活性的组分则没有存活能力。综上所述，这些结果表明ATA和EB在MCF-7细胞中的存活/增殖促进作用是通过IGF-IR信号通路转导的。
Aurintricarboxylic acid (ATA), an endonuclease inhibitor, prevents the death of a variety of cell types in culture. Previously we have shown that ATA, similar to insulin-like growth factor I (IGF-I), protected MCF-7 cells against apoptotic death induced by the protein synthesis inhibitor cycloheximide. Here we show that ATA and a polysulfonated aromatic compound, Evans blue (EB), similar to IGF-I, promote survival and increase proliferation of MCF-7 cells in serum-free culture medium. This may suggest a common signaling pathway shared by the aromatic polyanions and IGF-I. Therefore, the ability of these aromatic compounds to activate the signal transduction pathway of IGF-I was examined. We found that ATA and EB mimicked the IGF-I effect on tyrosine phosphorylation of the IGF-I receptor (IGF-IR) and its major substrates, insulin receptor substrate-1 (IRS-1) and IRS-P: induced the association of these substrates with phosphatidylinositol 3-kinase and Grb2; and activated Akt kinase and p42/p44 mitogen-activated protein kinases. ATA and EB competed for IGF-I binding to the IGF-IR. ATA was found to be selective for the IGF-IR, whereas EB also activated the insulin receptor. Upon fractionation of commercial ATA by size exclusion chromatography, we found that fractions that enhanced the intensity of tyrosyl-phosphorylated IRS-1/IRS-2 also increased the survival of MCF-7 cells in the presence of cycloheximide, whereas fractions devoid of IRS phosphorylation activity had no survival ability. Taken together, these results suggest that the survival/proliferation-promoting effects of ATA and EB in MCF-7 cells are transduced via the IGF-IR signaling pathway.