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Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells

机译：丝氨酸饥饿诱导癌细胞中的应激和p53依赖的代谢重塑

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摘要

肿瘤抑制因子p53在几个应激反应通道中发挥rn功能。现在，Karerl Vousden及其同事报告，rnp53还通过限制增殖以及将丝氨酸代谢导向谷rn胱甘肽的生成和活性氧的限制来帮助细胞在rn丝氨酸被耗尽的条件下能够生存。没有p53的rn细胞不能发生这些适应性变化，对于丝氨酸rn被耗尽(的状况)也要脆弱得多。这些发现被rn用来演示，一种不含丝氨酸的饮食能减少p53rn缺失性肿瘤在一个小鼠模型中的生长。这项rn工作表明，丝氨酸被耗尽(通过将其从饮食中rn除去、通过酶使其耗尽或通过其他一些手段rn使其耗尽)作为一个可能的治疗方法值得进一rn步研究。%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 (also known as TP53) influences a range of cellular metabolic processes, including glycolysis, oxidative phosphorylation, gluta-minolysis 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 human cancer cells rapidly use exogenous serine and that serine deprivation triggered activation of the serine synthesis pathway and rapidly suppressed aerobic glycolysis, resulting in an increased flux to the tricarboxylic acid cycle. Transient p53-p21 (also known as CDKN1A) activation and cell-cycle arrest promoted cell survival by efficiently channelling depleted serine stores to glutathione synthesis, thus 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, indicating that serine depletion has a potential role in the treatment of p53-deficient tumours.
机译：肿瘤抑制因子p53在几个应激反应通道中发挥rn功能。现在，Karerl Vousden及其同事报告，rnp53还通过限制增殖以及将丝氨酸代谢导向谷rn胱甘肽的生成和活性氧的限制来帮助细胞在rn丝氨酸被耗尽的条件下能够生存。没有p53的rn细胞不能发生这些适应性变化，对于丝氨酸rn被耗尽(的状况)也要脆弱得多。这些发现被rn用来演示，一种不含丝氨酸的饮食能减少p53rn缺失性肿瘤在一个小鼠模型中的生长。这项rn工作表明，丝氨酸被耗尽(通过将其从饮食中rn除去、通过酶使其耗尽或通过其他一些手段rn使其耗尽)作为一个可能的治疗方法值得进一rn步研究。%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 (also known as TP53) influences a range of cellular metabolic processes, including glycolysis, oxidative phosphorylation, gluta-minolysis 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 human cancer cells rapidly use exogenous serine and that serine deprivation triggered activation of the serine synthesis pathway and rapidly suppressed aerobic glycolysis, resulting in an increased flux to the tricarboxylic acid cycle. Transient p53-p21 (also known as CDKN1A) activation and cell-cycle arrest promoted cell survival by efficiently channelling depleted serine stores to glutathione synthesis, thus 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, indicating that serine depletion has a potential role in the treatment of p53-deficient tumours.

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  • 来源
    《Nature》 |2013年第7433期|542-546a3|共6页
  • 作者

    Oliver D. K. Maddocks; Celia R. Berkers; Susan M. Mason; Liang Zheng; Karen Blyth; Eyal Gottlieb; Karen H. Vousden;

  • 作者单位

    The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK.;

    The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK.;

    The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK.;

    The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK.;

    The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK.;

    The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK.;

    The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK.;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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