Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells.
Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells.
复制标题
丝氨酸饥饿诱导癌细胞中的应激和p53依赖性代谢重塑。
DOI：
10.1038/nature11743
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发表时间：
2013-01-24
期刊：
影响因子：
64.8
通讯作者：
Vousden KH
中科院分区：
文献类型：
--
作者：
Maddocks OD;Berkers CR;Mason SM;Zheng L;Blyth K;Gottlieb E;Vousden KH
癌细胞获得不同的代谢适应，以生存与肿瘤生长相关的压力，并满足增殖的合成代谢需求。肿瘤抑制蛋白p53影响一系列细胞代谢过程，包括糖酵解、氧化磷酸化（OXPHOS）、精氨酸分解和抗氧化反应。与其在DNA损伤应激期间促进细胞凋亡的作用相反，p53可以在代谢应激期间促进细胞存活，这一功能不仅有助于肿瘤抑制，而且有助于p53的非癌症相关功能。在这里，我们表明，癌细胞迅速利用外源性丝氨酸和丝氨酸剥夺触发激活的丝氨酸合成途径（SSP）和快速抑制有氧糖酵解，导致增加流量的TCA循环。瞬时p53-p21激活和细胞周期停滞促进细胞存活，有效地将耗尽的丝氨酸储存引导至谷胱甘肽合成，保留细胞的抗氧化能力。缺乏p53的细胞无法完成对丝氨酸耗竭的反应，导致氧化应激，活力降低和严重受损的增殖。p53在丝氨酸饥饿条件下支持癌细胞增殖的作用被转化为体内模型，表明丝氨酸耗竭在治疗p53缺陷型肿瘤中具有潜在作用。
Cancer cells acquire distinct metabolic adaptations to survive stress associated with tumour growth and to satisfy the anabolic demands of proliferation. The tumour suppressor protein p53 influences a range of cellular metabolic processes, including glycolysis oxidative phosphorylation (OXPHOS), glutaminolysis and anti-oxidant response. In contrast to its role in promoting apoptosis during DNA damaging stress, p53 can promote cell survival during metabolic stress, a function that may contribute not only to tumour suppression but also to non-cancer associated functions of p53. Here we show that cancer cells rapidly utilise exogenous serine and that serine deprivation triggered activation of the serine synthesis pathway (SSP) and rapidly suppressed aerobic glycolysis, resulting in increased flux to the TCA cycle. Transient p53-p21 activation and cell cycle arrest promoted cell survival efficiently channelling depleted serine stores to glutathione synthesis, preserving cellular anti-oxidant capacity. Cells lacking p53 failed to complete the response to serine depletion, resulting in oxidative stress, reduced viability and severely impaired proliferation. The role of p53 in supporting cancer cell proliferation under serine starvation was translated to an in vivo model, suggesting that serine depletion has a potential role in the treatment of p53-deficient tumours.