Autophagy. 2012 Jan;8(1):1-3. doi: 10.4161/auto.8.1.16618. Epub 2012 Jan 1.
In the mammalian system, cell death is often preceded or accompanied by autophagic vacuolization, a finding that initially led to the widespread belief that so-called "autophagic cell death" would be mediated by autophagy. Thanks to the availability of genetic tools to disable the autophagic machinery, it has become clear over recent years that autophagy usually constitutes a futile attempt of dying cells to adapt to lethal stress rather than a mechanism to execute a cell death program. Recently, we systematically addressed the question as to whether established or prospective anticancer agents may induce "autophagic cell death". Although a considerable portion among the 1,400 compounds that we evaluated induced autophagic puncta and actually increased autophagic flux, not a single one turned out to kill tumor cells through the induction of autophagy. Thus, knockdown of essential autophagy genes (such as ATG5 and ATG7) failed to prevent and rather accelerated chemotherapy-induced cell death, in spite of the fact that this manipulation efficiently inhibits autophagosome formation. Herein, we review these finding and--polemically--raise doubts as to the very existence of "autophagic cell death".
在哺乳动物系统中，细胞死亡通常伴随着自噬空泡化，这一发现最初导致人们普遍认为所谓的“自噬细胞死亡”将由自噬介导。近年来，由于有了可以使自噬机制失活的遗传工具，人们越来越清楚地认识到，自噬通常是垂死细胞适应致命应激的徒劳尝试，而不是执行细胞死亡程序的机制。最近，我们系统地研究了一个问题，即已确立或潜在的抗癌药物是否会诱导“自噬细胞死亡”。尽管我们评估的 1400 种化合物中有相当一部分诱导了自噬点状结构，实际上增加了自噬通量，但没有一种通过诱导自噬来杀死肿瘤细胞。因此，尽管这种操作能有效地抑制自噬体的形成，但敲除必需的自噬基因（如 ATG5 和 ATG7）不仅未能阻止，反而加速了化疗诱导的细胞死亡。在此，我们回顾这些发现，并对“自噬细胞死亡”的存在提出质疑。
