A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence.
A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence.
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DOI：
10.1038/cddiscovery.2017.75
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发表时间：
2017
影响因子：
7
通讯作者：
Kron SJ
中科院分区：
文献类型：
--
作者：
Flor AC;Wolfgeher D;Wu D;Kron SJ
在其增殖极限，正常细胞停滞并经历复制性衰老，表现出大细胞尺寸、扁平形态和衰老相关的β-半乳糖苷酶（SA-β-Gal）活性。暴露于遗传毒性应激的正常或肿瘤细胞经历治疗诱导的衰老（TIS），表现出相似的表型。衰老被认为是一种DNA损伤反应，但细胞异质性阻碍了衰老特异性标记物和靶标的鉴定。为了探索衰老细胞蛋白质组，我们用依托泊苷处理肿瘤细胞，并通过荧光激活细胞分选（FACS）富集SA-β-GalHI细胞。通过无标记定量LC-MS/MS蛋白质组学和系统分析，将富集的TIS细胞与增殖或静止细胞进行比较，揭示多种脂质代谢途径的激活。衰老细胞积累的脂滴和进口脂质示踪剂，而治疗增殖细胞与特定的脂质诱导衰老。衰老细胞还显示脂质醛和醛解毒酶的上调。这些结果将脂质代谢失调与遗传毒性应激一起作为调节细胞衰老的因素。
At their proliferative limit, normal cells arrest and undergo replicative senescence, displaying large cell size, flat morphology, and senescence-associated beta-galactosidase (SA-β-Gal) activity. Normal or tumor cells exposed to genotoxic stress undergo therapy-induced senescence (TIS), displaying a similar phenotype. Senescence is considered a DNA damage response, but cellular heterogeneity has frustrated identification of senescence-specific markers and targets. To explore the senescent cell proteome, we treated tumor cells with etoposide and enriched SA-β-GalHI cells by fluorescence-activated cell sorting (FACS). The enriched TIS cells were compared to proliferating or quiescent cells by label-free quantitative LC-MS/MS proteomics and systems analysis, revealing activation of multiple lipid metabolism pathways. Senescent cells accumulated lipid droplets and imported lipid tracers, while treating proliferating cells with specific lipids induced senescence. Senescent cells also displayed increased lipid aldehydes and upregulation of aldehyde detoxifying enzymes. These results place deregulation of lipid metabolism alongside genotoxic stress as factors regulating cellular senescence.
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