Level of macroautophagy drives senescent keratinocytes into cell death or neoplastic evasion.
Level of macroautophagy drives senescent keratinocytes into cell death or neoplastic evasion.
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DOI：
10.1038/cddis.2014.533
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发表时间：
2014-12-18
影响因子：
9
通讯作者：
Abbadie C
中科院分区：
文献类型：
--
作者：
Deruy E;Nassour J;Martin N;Vercamer C;Malaquin N;Bertout J;Chelli F;Pourtier A;Pluquet O;Abbadie C
衰老是正常细胞响应各种应激（包括端粒脱帽、氧化应激或癌基因激活）而达到的一种非增殖状态。在之前的报告中，我们强调衰老的人类表皮角质形成细胞有两种相反的结果：要么通过自噬性程序性细胞死亡而死亡，要么以肿瘤性衰老后突现（PSNE）细胞的形式逃避。在此，我们表明，使用 3-甲基腺嘌呤或抗 Atg5 siRNA 部分减少衰老角质形成细胞中的巨自噬会增加 PSNE 频率，表明衰老角质形成细胞必须逃避自噬细胞死亡才能产生 PSNE 细胞。然而，完全抑制巨自噬会损害 PSNE 并导致氧化损伤大量积累，表明衰老角质形成细胞需要实现巨自噬的质量控制才能发生 PSNE。因此，我们证明 PSNE 细胞祖细胞的巨自噬水平略低于平均衰老细胞群的水平，这直接取决于其活性氧水平、MnSOD 上调水平、NF-κB 转录因子激活水平以及功能失调的线粒体水平。因此，巨自噬在衰老过程中具有拮抗作用，根据其激活水平诱导细胞死亡或促进肿瘤转化。综上所述，这些数据表明，氧化损伤水平和随后的巨自噬活性可能是通过衰老逃避进行肿瘤转化的最初阶段的两个主要决定因素。
Senescence is a non-proliferative state reached by normal cells in response to various stresses, including telomere uncapping, oxidative stress or oncogene activation. In previous reports, we have highlighted that senescent human epidermal keratinocytes have two opposite outcomes: either they die by autophagic programmed cell death or they evade in the form of neoplastic postsenescence emergent (PSNE) cells. Herein, we show that partially reducing macroautophagy in senescent keratinocytes using 3-methyl adenine or anti-Atg5 siRNAs increases the PSNE frequency, suggesting that senescent keratinocytes have to escape autophagic cell death to generate PSNE cells. However, totally inhibiting macroautophagy impairs PSNE and leads to a huge accumulation of oxidative damages, indicating that senescent keratinocytes need to achieve quality-control macroautophagy for PSNE to occur. In accordance, we demonstrate that the progenitors of PSNE cells display a level of macroautophagy slightly lower than that of the average senescent population, which is directly dictated by their level of reactive oxygen species, their level of upregulation of MnSOD, their level of activation of NF-κB transcription factors and their level of dysfunctional mitochondria. Macroautophagy thus has antagonistic roles during senescence, inducing cell death or promoting neoplastic transformation, depending on its level of activation. Taken together, these data suggest that levels of oxidative damages and ensuing macroautophagic activity could be two main determinants of the very initial phases of neoplastic transformation by senescence evasion.