INSERM, U848, Villejuif, France.
Oncogene. 2011 Nov 10;30(45):4544-56. doi: 10.1038/onc.2011.168. Epub 2011 May 16.
To address the question of whether established or experimental anticancer chemotherapeutics can exert their cytotoxic effects by autophagy, we performed a high-content screen on a set of cytotoxic agents. We simultaneously determined parameters of autophagy, apoptosis and necrosis on cells exposed to -1400 compounds. Many agents induced a 'pure' autophagic, apoptotic or necrotic phenotype, whereas less than 100 simultaneously induced autophagy, apoptosis and necrosis. A systematic analysis of the autophagic flux induced by the most potent 80 inducers of GFP-LC3 puncta among the NCI panel agents showed that 59 among them truly induced autophagy. The remaining 21 compounds were potent inducers of apoptosis or necrosis, yet failed to stimulate an autophagic flux, which were characterized as microtubule inhibitors. Knockdown of ATG7 was efficient in preventing GFP-LC3 puncta, yet failed to attenuate cell death by the agents that induce GFP-LC3 puncta. Thus there is not a single compound that would induce cell death by autophagy in our screening, underscoring the idea that cell death is rarely, if ever, executed by autophagy in human cells.
为了探讨已确立或实验性的抗癌化学疗法是否能通过自噬发挥其细胞毒性作用，我们对一组细胞毒性药物进行了高通量筛选。我们同时在暴露于-1400 种化合物的细胞中测定了自噬、凋亡和坏死的参数。许多药物诱导出“纯”自噬、凋亡或坏死表型，而不到 100 种药物同时诱导自噬、凋亡和坏死。对 NCI 面板药物中 GFP-LC3 斑点最有效的 80 种诱导剂所诱导的自噬流的系统分析表明，其中 59 种确实诱导了自噬。其余 21 种化合物是凋亡或坏死的有效诱导剂，但未能刺激自噬流，它们被认为是微管抑制剂。ATG7 的敲低有效地阻止了 GFP-LC3 斑点的形成，但未能减轻诱导 GFP-LC3 斑点形成的药物引起的细胞死亡。因此，在我们的筛选中没有一种化合物会通过自噬诱导细胞死亡，这强调了一个观点，即在人类细胞中，细胞死亡很少（如果有的话）是通过自噬来执行的。
