Autophagy in Hypoxia Protects Cancer Cells Against Apoptosis Induced by Nutrient Deprivation Through a Beclin1-Dependent Way in Hepatocellular Carcinoma
Autophagy in Hypoxia Protects Cancer Cells Against Apoptosis Induced by Nutrient Deprivation Through a Beclin1-Dependent Way in Hepatocellular Carcinoma
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缺氧中的自噬通过 Beclin1 依赖性方式在肝细胞癌中保护癌细胞免受营养剥夺诱导的细胞凋亡
DOI：
10.1002/jcb.23274
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发表时间：
2011-11-01
影响因子：
4
通讯作者：
Wei, Lixin
中科院分区：
文献类型：
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作者：
Song, Jianrui;Guo, Xianling;Wei, Lixin
由于血液供应不良，实体瘤中普遍存在缺氧和营养缺乏的情况。然而，癌细胞却能在这种不利条件下存活下来并不断增殖发展。为了找出生存之道，我们研究了自噬在肝细胞癌微环境中的作用。为了更真实地模拟肿瘤微环境，细胞在缺氧预处理后在缺氧、缺氧的条件下培养。结果，缺氧加营养剥夺下的细胞死亡比仅营养剥夺下的细胞死亡少得多。细胞死亡的减少主要归因于细胞凋亡的减少。 GFP-LC3和电镜分析显示缺氧预处理期间自噬显着激活。然而，自噬抑制剂-3-MA显着消除了缺氧时细胞凋亡的减少，这表明自噬参与保护肝细胞癌细胞免受饥饿诱导的细胞凋亡。此外，Beclin 1 被证明在此过程中发挥了重要作用。靶向 Beclin 1 的 siRNA 被转染至肝细胞癌细胞中。 Western blot检测LC3-II表达和透射显微镜观察自噬体积累的数据均表明，Beclin 1敲低后自噬受到明显抑制。此外，缺氧条件下饥饿细胞的凋亡减少也被逆转。综上所述，这些结果表明缺氧激活的自噬介导了肝细胞癌细胞对营养剥夺的耐受性，并且这种耐受性依赖于Beclin 1. J. Cell的活性。生物化学。 112：3406-3420，2011。(C)2011 Wiley 期刊公司。
Oxygen deficiency and nutrient deprivation widely exists in solid tumors because of the poor blood supply. However, cancer cells can survive this adverse condition and proliferate continuously to develop. To figure out the way to survive, we investigated the role of autophagy in the microenvironment in hepatocellular carcinoma. In order to simulate the tumor microenvironment more veritably, cells were cultured in oxygen-nutrient-deprived condition following a hypoxia preconditioning. As a result, cell death under hypoxia plus nutrient deprivation was much less than that under nutrient deprivation only. And the decreased cell death mainly attributed to the decreased apoptosis. GFP-LC3 and electron microscopy analysis showed that autophagy was significantly activated in the period of hypoxia preconditioning. However, autophagic inhibitor-3-MA significantly abrogated the apoptosis reduction in hypoxia, which implied the involvement of autophagy in protection of hepatocellular carcinoma cells against apoptosis induced by starvation. Furthermore, Beclin 1 was proved to play an important role in this process. siRNA targeting Beclin 1 was transfected into hepatocellular carcinoma cells. And both data from western blot detecting the expression of LC3-II and transmission microscopy observing the accumulation of autophagosomes showed that autophagy was inhibited obviously as a result of Beclin 1 knockdown. Besides, the decreased apoptosis of starved cells under hypoxia was reversed. Taken together, these results suggest that autophagy activated by hypoxia mediates the tolerance of hepatocellular carcinoma cells to nutrient deprivation, and this tolerance is dependent on the activity of Beclin 1. J. Cell. Biochem. 112: 3406-3420, 2011. (C) 2011 Wiley Periodicals, Inc.