Detach ment-induced autophagy during anoikis and lumen formation in epithelial acini
Detach ment-induced autophagy during anoikis and lumen formation in epithelial acini
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DOI：
10.4161/auto.5523
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发表时间：
2008-04-01
期刊：
影响因子：
13.3
通讯作者：
Debnath, Jayanta
中科院分区：
文献类型：
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作者：
Debnath, Jayanta
由腺上皮组成的单个单位(称为腺泡)拥有一个中空的管腔，在早期的上皮性癌中被填充。在使用体外三维(3D)上皮细胞培养模型研究这种中空管腔的形成时，我们观察到在管腔形成过程中死亡细胞中广泛的自噬，因此提出过度的自食可能促进管腔内的细胞死亡。然而，我们现在重新评估了这一假设。由于腔内细胞由于细胞外基质(ECM)缺失而死亡，我们测试了自噬是否受ECM脱离的调节。我们发现，即使Bc1-2的表达抑制了细胞的凋亡，脱离也会强烈地诱导上皮细胞的自噬。RNAi介导的自噬相关(ATG)基因的缺失抑制了脱离诱导的自噬，导致细胞凋亡增加和失巢后克隆形成恢复减少。类似地，在3D形态发生过程中，ATG-耗竭增强了管腔的凋亡，即使与细胞凋亡抑制相结合，也不能诱导长期的管腔存活和充盈。因此，在失巢失巢过程中，自噬促进了上皮细胞的存活。这些结果提出了自噬有助于缺乏适当基质接触的肿瘤细胞存活的可能性，无论是在癌症形成的早期阶段还是在扩散和转移的后期阶段。
The individual units (called acini) comprising glandular epithelium possess a hollow lumen that is filled in early epithelial cancers. While investigating the generation of this hollow lumen using an in vitro three-dimensional (3D) epithelial cell culture model, we observed extensive autophagy in dying cells during lumen formation, and thus, proposed that excessive self-eating may promote cell death in the lumen. However, we now reassess this hypothesis. Because cells in the lumen die due to extracellular matrix (ECM) deprivation (anoikis), we tested if autophagy is regulated by ECM detachment. We discovered that detachment strongly induces autophagy in epithelial cells, even when apoptosis is inhibited by Bc1-2 expression. RNAi-mediated depletion of autophagy-related (ATG) genes inhibits detachment-induced autophagy, resulting in increased apoptosis and reduced clonogenic recovery following anoikis. Similarly, during 3D morphogenesis, ATG-depletion enhances luminal apoptosis and fails to elicit long-term luminal survival and filling, even when combined with apoptotic inhibition. Thus, autophagy promotes epithelial cell survival during anoikis. These results broach the possibility that autophagy contributes to the survival of tumor cells lacking appropriate matrix contact, either during early carcinoma formation or in the later stages of dissemination and metastasis.