The Novel mTOR Complex 1/2 Inhibitor P529 Inhibits Human Lung Myofibroblast Differentiation.
The Novel mTOR Complex 1/2 Inhibitor P529 Inhibits Human Lung Myofibroblast Differentiation.
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新型MTOR复合物1/2抑制剂P529抑制人肺肌纤维细胞分化。
DOI：
10.1002/jcb.25878
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发表时间：
2017-08
影响因子：
4
通讯作者：
Sandbo N
中科院分区：
文献类型：
--
作者：
Ferguson KT;Torr EE;Bernau K;Leet J;Sherris D;Sandbo N
特发性肺纤维化是一种进行性和致命的疾病，治疗选择很少。Palomid 529（8-（1-hydroxyethyl）-2-methoxy-3-（4-methoxybenzyloxy）-benzo[c]chromen-6-one; P529）是一种新型的雷帕霉素复合物1/2（mTORC 1/2）机制靶点双重抑制剂。在这些研究中，我们研究了P529对TGF-β依赖性信号传导和肌成纤维细胞分化的影响。在人肺成纤维细胞中，TGF-β诱导的mTORC 1靶点p70 S6激酶1（S6 K1）和真核翻译起始因子4 E结合蛋白1（4 E-BP 1）的磷酸化均受到P529的剂量依赖性抑制，最大抑制发生在10-20 μM之间。与TGF-β诱导的肌成纤维细胞分化一样，mTORC 2介导的Akt在S473位点的磷酸化被部分抑制，具有类似的剂量依赖性。TGF-β诱导的纤连蛋白和胶原蛋白的蛋白水平也被P529类似地降低。在该剂量下，Col 1和α-SMA的mRNA转录水平也受到抑制，表明转录激活受到抑制。然而，通过受体相关的Smad 2/3磷酸化、Smad 2/3/4易位或通过Smad结合元件驱动的荧光素酶评估的Smad驱动的基因表达，P529对典型的TGF-β诱导的Smad信号传导没有影响。相反，mTORC 1/2信号传导的激活依赖于TGF-β I型受体（ALK 5）信号传导和Smad 2/3表达。P529处理破坏了肌成纤维细胞分化过程中TGF-β诱导的肌动蛋白应力纤维的形成、新的细胞外纤连蛋白基质的沉积以及成纤维细胞的线性伤口闭合。同样，mTOR敲低抑制TGF-β诱导的肌成纤维细胞分化。总之，P529抑制TGF-β诱导的肌成纤维细胞分化、肌动蛋白应力纤维形成以及基质蛋白表达和沉积。通过P529抑制mTORC 1/2可能是抑制体内纤维化的有希望的方法。
Idiopathic pulmonary fibrosis is a progressive and deadly disorder with very few therapeutic options. Palomid 529 (8-(1-hydroxyethyl)-2-methoxy-3-(4-methoxybenzyloxy)-benzo[c]chromen-6-one; P529) is a novel dual inhibitor of mechanistic target of rapamycin complex 1/2 (mTORC1/2). In these studies, we investigated the effect of P529 on TGF-β-dependent signaling and myofibroblast differentiation. TGF-β-induced phosphorylation of the mTORC1 targets, p70 S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), were both dose dependently inhibited by P529 in human lung fibroblasts with maximal inhibition occurring between 10–20 μM. mTORC2-mediated phosphorylation of Akt at the S473 site was partially inhibited with a similar dose dependency, as was TGF-β-induced myofibroblast differentiation. Protein levels of TGF-β-induced fibronectin and collagen were similarly decreased by P529. At this dose, there was also inhibition of mRNA transcript levels for Col1 and α-SMA, suggesting inhibition of transcriptional activation. However, there was no effect of P529 on canonical TGF-β-induced Smad signaling, as assessed by receptor-associated Smad2/3 phosphorylation, Smad2/3/4 translocation, or Smad-driven gene expression, as assessed by Smad-binding element driven luciferase. Conversely, activation of mTORC1/2 signaling was dependent on TGF-β type I receptor (ALK5) signaling and on Smad2/3 expression. P529 treatment disrupted TGF-β-induced actin stress fiber formation during myofibroblast differentiation, the deposition of new extracellular fibronectin matrix, and linear wound closure by fibroblasts. Likewise, mTOR knockdown inhibited TGF-β-induced myofibroblast differentiation. In conclusion, P529 inhibits TGF-β-induced myofibroblast differentiation, actin stress fiber formation, and matrix protein expression and deposition. Inhibition of mTORC1/2 by P529 may be a promising approach to inhibit in vivo fibrosis.
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DOI：
10.1016/j.trsl.2011.05.004
发表时间：
2011-10
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Sandbo N;Dulin N
通讯作者：
Dulin N
DOI：
10.1084/jem.20080001
发表时间：
2008-07-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Xia H;Diebold D;Nho R;Perlman D;Kleidon J;Kahm J;Avdulov S;Peterson M;Nerva J;Bitterman P;Henke C
通讯作者：
Henke C
影响因子：
8
作者：
Xiang, T.;Jia, Y.;Sherris, D.;Li, S.;Wang, H.;Lu, D.;Yang, Q.
通讯作者：
Yang, Q.
DOI：
10.1165/rcmb.2003-0063oc
发表时间：
2003-09-01
影响因子：
6.4
作者：
Hu, B;Wu, Z;Phan, SH
通讯作者：
Phan, SH
影响因子：
3.3
作者：
Zhang, QH;Magnusson, MK;Mosher, DF
通讯作者：
Mosher, DF