Simon Hans-Uwe, Friis Robert
Institute of Pharmacology; University of Bern; Bern, Switzerland.
Autophagy. 2014 Jan;10(1):176-7. doi: 10.4161/auto.26916. Epub 2013 Nov 18.
Both apoptotic and autophagic pathways are activated in cells during anticancer treatment using DNA-damaging agents. Thus, the outcome is balanced between apoptotic cell death and enhanced autophagy, with the possibility of prolonged cell survival. It seems intuitively obvious that this survival mechanism might interfere with the desired tumor cell killing. We addressed this question by tipping the balance in favor of autophagy, using etoposide or cisplatin at low, sublethal doses. Over 4 days, only a little apoptosis was observed, but both drugs sharply increased autophagic flux. Surprisingly, cells underwent a cell cycle arrest at G 2/M, followed later by mitotic catastrophe with formation of multipolar spindles, missegregated chromosomes, or enlarged, irregular, sometimes multiple nuclei. Why? The answer is that even a low level of DNA damage not only upregulates autophagy, but also provokes the recruitment of an autophagy-related protein, ATG5, to the nucleus, where it binds BIRC5/survivin, thereby interfering with correct assembly of the chromosome passenger complex needed for cytokinesis.
在使用DNA损伤剂进行抗癌治疗期间，细胞内的凋亡和自噬途径均被激活。因此，结果是凋亡性细胞死亡与自噬增强之间达到平衡，细胞有可能长期存活。直观来看，这种存活机制可能会干扰预期的肿瘤细胞杀伤效果。我们通过使用低剂量、亚致死剂量的依托泊苷或顺铂使平衡偏向自噬，来解决这个问题。在4天的时间里，仅观察到少量凋亡，但这两种药物均显著增加了自噬通量。令人惊讶的是，细胞在G2/M期发生细胞周期阻滞，随后出现有丝分裂灾难，形成多极纺锤体、染色体错配或细胞核增大、形态不规则，有时还会出现多个细胞核。原因何在？答案是即使是低水平的DNA损伤不仅会上调自噬，还会促使一种自噬相关蛋白ATG5募集到细胞核，在细胞核中它与BIRC5/生存素结合，从而干扰胞质分裂所需的染色体乘客复合体的正确组装。
