AMDE-1 is a dual function chemical for autophagy activation and inhibition.
AMDE-1 is a dual function chemical for autophagy activation and inhibition.
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DOI：
10.1371/journal.pone.0122083
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Yin XM
中科院分区：
文献类型：
--
作者：
Li M;Yang Z;Vollmer LL;Gao Y;Fu Y;Liu C;Chen X;Liu P;Vogt A;Yin XM
自噬是细胞质组分和细胞器被递送到溶酶体进行降解的过程。自噬在细胞内环境稳定和疾病发病机制中起重要作用。能够调节自噬活性的小化学分子可能具有治疗疾病的药理学价值。使用基于GFP-LC 3的高含量筛选试验，我们发现了一种能够在起始和降解水平调节自噬的新型化学物质。这种分子被称为具有双重效应的自噬调节剂-1（AMDE-1），以Atg 5依赖性方式触发自噬，将Atg 16募集到自噬体前位点并引起LC 3脂化。AMDE-1通过激活AMPK诱导自噬，AMPK灭活mTORC 1并激活ULK 1。AMDE-1不影响MAP激酶、JNK或氧化应激信号传导诱导自噬。令人惊讶的是，用AMDE-1处理导致自噬通量的损害和长寿命蛋白质降解的抑制。这种抑制与溶酶体降解能力的降低相关，但与自噬体-溶酶体融合无关。进一步分析表明，AMDE-1导致溶酶体酸度和溶酶体蛋白水解活性降低，表明其抑制一般溶酶体功能。因此，AMDE-1也损害了内吞介导的EGF受体降解。AMDE-1对自噬诱导和溶酶体降解的双重作用表明，其净效应可能导致自噬应激和溶酶体功能障碍，从而导致细胞死亡。事实上，AMDE-1触发坏死性凋亡，并优先对癌细胞具有细胞毒性。总之，这项研究确定了一类新的具有双重作用的自噬调节剂，可以探索其在癌症治疗中的潜在用途。
Autophagy is the process by which cytosolic components and organelles are delivered to the lysosome for degradation. Autophagy plays important roles in cellular homeostasis and disease pathogenesis. Small chemical molecules that can modulate autophagy activity may have pharmacological value for treating diseases. Using a GFP-LC3-based high content screening assay we identified a novel chemical that is able to modulate autophagy at both initiation and degradation levels. This molecule, termed as Autophagy Modulator with Dual Effect-1 (AMDE-1), triggered autophagy in an Atg5-dependent manner, recruiting Atg16 to the pre-autophagosomal site and causing LC3 lipidation. AMDE-1 induced autophagy through the activation of AMPK, which inactivated mTORC1 and activated ULK1. AMDE-1did not affect MAP kinase, JNK or oxidative stress signaling for autophagy induction. Surprisingly, treatment with AMDE-1 resulted in impairment in autophagic flux and inhibition of long-lived protein degradation. This inhibition was correlated with a reduction in lysosomal degradation capacity but not with autophagosome-lysosome fusion. Further analysis indicated that AMDE-1 caused a reduction in lysosome acidity and lysosomal proteolytic activity, suggesting that it suppressed general lysosome function. AMDE-1 thus also impaired endocytosis-mediated EGF receptor degradation. The dual effects of AMDE-1 on autophagy induction and lysosomal degradation suggested that its net effect would likely lead to autophagic stress and lysosome dysfunction, and therefore cell death. Indeed, AMDE-1 triggered necroptosis and was preferentially cytotoxic to cancer cells. In conclusion, this study identified a new class of autophagy modulators with dual effects, which can be explored for potential uses in cancer therapy.
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影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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影响因子：
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