DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells
DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells
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DOI：
10.1038/sj.cdd.4402030
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发表时间：
2007-03-01
影响因子：
12.4
通讯作者：
Pieper, R. O.
中科院分区：
文献类型：
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作者：
Katayama, M.;Kawaguchi, T.;Pieper, R. O.
尽管自噬通过增加三磷酸腺苷（ATP）的产生来提高营养缺乏细胞的存活率，但自噬在细胞毒性化疗药物处理的细胞中是否具有类似功能仍不清楚。为了解决这个问题，我们测量了DNA损伤剂（替莫唑胺和依托泊苷）诱导自噬依赖性ATP产生的能力，以及自噬调节对药物诱导的细胞死亡的影响。这两种药物在多种神经胶质瘤细胞系中都诱导了与自噬相关的ATP产生增加。药物诱导的ATP激增不能被葡萄糖饥饿阻断，但可以被自噬抑制剂3 - 甲基腺嘌呤（3 - MA）、靶向beclin 1的小干扰RNA或线粒体抑制剂寡霉素预孵育所阻断。抑制自噬诱导的ATP产生会增加与微核形成相关的非凋亡性细胞死亡，而通过添加丙酮酸恢复被3 - MA抑制的ATP激增则会抑制细胞死亡。这些结果表明，DNA损伤剂诱导与自噬相关的ATP激增，这种激增保护细胞并可能导致耐药性。
Although autophagy enhances cell survival in nutrient-deprived cells by increasing adenosine triphosphate (ATP) production, it remains unclear if autophagy functions similarly in cells treated with cytotoxic chemotherapy agents. To address this issue, we measured both the ability of DNA damaging agents (Temozolomide, and Etoposide) to induce an autophagy-dependent production of ATP, and the effects of modulation of autophagy on drug-induced cell death. Both drugs induced an autophagy-associated increase in ATP production in multiple glioma cell lines. The drug-induced ATP surge could not be blocked by glucose starvation, but could be blocked by preincubation with the autophagy inhibitor 3-methyladenine (3-MA), an siRNA targeting beclin 1, or the mitochondrial inhibitor oligomycin. Inhibition of autophagy-induced ATP production increased nonapoptotic cell death associated with micronucleation, while restoration of the 3-MA-inhibited ATP surge by addition of pyruvate suppressed cell death. These results show that DNA damaging agents induce an autophagy-associated ATP surge that protects cells and may contribute to drug resistance.