Induction of prosurvival molecules by apoptotic stimuli: involvement of FOXO3a and ROS
Induction of prosurvival molecules by apoptotic stimuli: involvement of FOXO3a and ROS
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DOI：
10.1038/sj.onc.1208385
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发表时间：
2005-03-17
期刊：
影响因子：
8
通讯作者：
Tang, DG
中科院分区：
文献类型：
--
作者：
Liu, JW;Chandra, D;Tang, DG
大多数癌症疗法无法根除癌症，因为癌细胞迅速对其促凋亡作用产生耐药性。潜在的机制仍然不完全清楚。在这里，我们展示了三种具有代表性的凋亡刺激，即血清饥饿，线粒体毒素和dna损伤剂（etoposide），快速诱导几种不同类型的促生存分子，特别是Bcl-2/Bcl-X-L和超氧化物歧化酶（SOD，包括MnSOD和Cu/ZnSOD）。在群体水平上，这些促生存分子的诱导发生在促凋亡分子如Bim和Bak的诱导之前或同时发生。使用促生存分子或促凋亡分子的sirna阻断诱导分别促进或抑制细胞凋亡。其中一个主转录因子FOXO3a参与了一些促存活（如MnSOD）和促凋亡（如Bim）分子的转录激活。有趣的是，在所有三种凋亡系统中，FOXO3a本身也在转录水平上调。机制研究表明，细胞凋亡刺激可迅速诱导活性氧（ROS）， ROS抑制剂/清除剂可阻断FOXO3a、MnSOD和Bim的诱导。最后，我们发现凋亡刺激也上调正常二倍体人成纤维细胞和亚凋亡浓度下的促存活分子。综上所述，这些结果表明各种凋亡诱导剂可能通过ros激活的主转录因子（如FOXO3a）快速调动促生存机制。结果表明，有效的抗癌治疗可能需要将诱导凋亡和抑制生存策略结合起来。
Most cancer therapeutics fails to eradicate cancer because cancer cells rapidly develop resistance to its proapoptotic effects. The underlying mechanisms remain incompletely understood. Here we show that three representative apoptotic stimuli, that is, serum starvation, a mitochondrial toxin, and a DNA-damaging agent (etoposide), rapidly induce several distinct classes of prosurvival molecules, in particular, Bcl-2/Bcl-X-L and superoxide dismutase (SOD; including both MnSOD and Cu/ZnSOD). At the population level, the induction of these prosurvival molecules occurs prior to or concomitant with the induction of proapoptotic molecules such as Bim and Bak. Blocking the induction using siRNAs of the prosurvival or proapoptotic molecules facilitates or inhibits apoptosis, respectively. One master transcription factor, FOXO3a, is involved in the transcriptional activation of some of these prosurvival (e. g., MnSOD) and proapoptotic (e. g., Bim) molecules. Interestingly, in all three apoptotic systems, FOXO3a itself is also upregulated at the transcriptional level. Mechanistic studies indicate that reactive oxygen species (ROS) are rapidly induced upon apoptotic stimulation and that ROS inhibitors/scavengers block the induction of FOXO3a, MnSOD, and Bim. Finally, we show that apoptotic stimuli also upregulate prosurvival molecules in normal diploid human fibroblasts and at subapoptotic concentrations. Taken together, these results suggest that various apoptotic inducers may rapidly mobilize prosurvival mechanisms through ROS-activated master transcription factors such as FOXO3a. The results imply that effective anticancer therapeutics may need to combine both apoptosis-inducing and survival-suppressing strategies.