Neuritogenic Activity of Tetradecyl 2,3-Dihydroxybenzoate Is Mediated through the Insulin-Like Growth Factor 1 Receptor/Phosphatidylinositol 3 Kinase/Mitogen-Activated Protein Kinase Signaling Pathway
Neuritogenic Activity of Tetradecyl 2,3-Dihydroxybenzoate Is Mediated through the Insulin-Like Growth Factor 1 Receptor/Phosphatidylinositol 3 Kinase/Mitogen-Activated Protein Kinase Signaling Pathway
复制标题
DOI：
10.1124/mol.115.097758
复制
发表时间：
2015-08-01
影响因子：
3.6
通讯作者：
Qi, Jianhua
中科院分区：
文献类型：
--
作者：
Tang, Ruiqi;Gao, Lijuan;Qi, Jianhua
十四烷基2,3-二羟基苯甲酸酯（ABG-001）是一种衍生自神经源性龙胆苷的先导化合物。在本研究中，我们研究了ABG-001诱导大鼠肾上腺嗜铬细胞瘤细胞系（PC12）神经突生长的机制。胰岛素样生长因子1 （IGF-1）受体、磷脂酰肌醇3-激酶（PI3K）和细胞外信号调节激酶（ERK） 1/2的抑制剂可显著降低abg -001诱导的神经突生长。Western blot分析显示，ABG-001显著诱导IGF-1受体、蛋白激酶B （Akt）、ERK和cAMP响应元件结合蛋白（CREB）的磷酸化。添加相应的抑制剂可显著降低这些影响。我们还发现，蛋白激酶C抑制剂以及针对IGF-1受体的小干扰RNA减少了abg -001诱导的神经突生长。此外，与ABG-001一样，IGF-1也能诱导PC12细胞的神经突生长，低剂量的神经生长因子增强了ABG-001对神经突生长的影响。这些结果表明，ABG-001靶向IGF-1受体，激活PI3K、丝裂原活化蛋白激酶及其下游信号级联，诱导神经突生长。
Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from neuritogenic gentisides. In the present study, we investigated the mechanism by which ABG-001 induces neurite outgrowth in a rat adrenal pheochromocytoma cell line (PC12). Inhibitors of insulin-like growth factor 1 (IGF-1) receptor, phosphatidylinositol 3-kinase (PI3K), and extracellular signal-regulated kinase (ERK) 1/2 significantly decreased ABG-001-induced neurite outgrowth. Western blot analysis revealed that ABG-001 significantly induced phosphorylation of IGF-1 receptor, protein kinase B (Akt), ERK, and cAMP responsive element-binding protein (CREB). These effects were markedly reduced by addition of the corresponding inhibitors. We also found that ABG-001-induced neurite outgrowth was reduced by protein kinase C inhibitor as well as small-interfering RNA against the IGF-1 receptor. Furthermore, like ABG-001, IGF-1 also induced neurite outgrowth of PC12 cells, and low-dose nerve growth factor augmented the observed effects of ABG-001 on neurite outgrowth. These results suggest that ABG-001 targets the IGF-1 receptor and activates PI3K, mitogen-activated protein kinase, and their downstream signaling cascades to induce neurite outgrowth.