Anoxia is necessary for tumor cell toxicity caused by a low-oxygen environment
Anoxia is necessary for tumor cell toxicity caused by a low-oxygen environment
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DOI：
10.1158/0008-5472.can-04-3395
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发表时间：
2005-04-15
期刊：
影响因子：
11.2
通讯作者：
Denko, NC
中科院分区：
文献类型：
--
作者：
Papandreou, I;Krishna, C;Denko, NC
体外暴露于缺氧的细胞已显示出减少增殖和/或参与程序性细胞死亡。关于缺氧诱导因子-1（HIF-1）和HIF-1靶基因在启动这些反应中的作用，文献中存在相当大的争议。因此，我们研究了氧依赖性和缺氧反应性转录因子HIF-1在细胞死亡决定中的作用。尽管适当诱导了HIF-1靶基因，但低至0.5%的氧浓度并不改变HIF-1-熟练或HIF-1-缺陷的鼠成纤维细胞或人肿瘤细胞的生长。严重缺氧（< 0.01%氧）确实诱导细胞凋亡，导致集落形成减少、染色质浓缩、DNA片段化和半胱天冬酶激活，但也与HIF α状态无关。因此，参与细胞死亡的HIF-1依赖性基因puplex（如BNip 3和BNip 3L）的转录诱导与缺氧依赖性毒性无关。同样，在几种人肿瘤细胞系中，强制过表达不可降解形式的HIF-1 α在常氧条件下不足以诱导细胞凋亡。总之，这些发现表明，额外的分子事件是由缺氧以HIF-1独立的方式触发的，这些变化是在低氧环境中观察到的细胞死亡所必需的。
Cells exposed to oxygen deprivation in vitro have been shown to reduce proliferation and/or engage in programmed cell death. There is considerable controversy in the literature as to the role of hypoxia-inducible factor-1 (HIF-1) and HIF-1 target genes in initiating these responses. We therefore examined the oxygen dependence and the role of the hypoxia-responsive transcription factor HIF-1 in making the cellular death decision. Oxygen concentrations as low as 0.5% did not alter the growth of HIF-1-proficient or HIF-1-deficient murine fibroblasts, or human tumor cells, despite the appropriate induction of HIF-1 target genes. Severe hypoxia (< 0.01% oxygen) did induced apoptosis, resulting in decreased colony formation, chromatin condensation, DNA fragmentation, and caspase activation but also independent of HIF alpha status. Transcriptional induction of HIF-1-dependent genes putatively involved in cell death like BNip3 and BNip3L was therefore disassociated from hypoxia-dependent toxicity. Likewise, forced overexpression of a nondegradable form of HIF-1 alpha in several human tumor cell lines was not sufficient to induce apoptosis under normoxic conditions. Taken together, these findings indicate that additional molecular events are triggered by anoxia in a HIF-1-independent manner, and these changes are necessary for cell death observed in low-oxygen environments.