Nature: 饮食中限制氨基酸蛋氨酸可以减少肿瘤生长

根据本周在线发表在《自然》杂志上的一篇论文，饮食中限制氨基酸蛋氨酸可以减少肿瘤生长，改善小鼠化疗和放疗的结果。在人类的一项原理验证研究中，饮食蛋氨酸水平的降低对新陈代谢的影响与小鼠相似，这可能表明人类和小鼠对这种氨基酸的饮食限制存在保守性。

甲硫氨酸是一种必需氨基酸(身体不能产生它)，在新陈代谢中起着关键作用。它作为一组称为单碳代谢的反应的一部分被代谢，这也是许多癌症治疗的目标，包括化疗和放疗。然而，还不清楚特定的饮食干预是否会影响这些疗法所针对的代谢途径。

Jason Locasale和他的同事研究了通过与其他针对一碳代谢的疗法相互作用，饮食限制蛋氨酸是否具有抗癌特性。在一系列小鼠癌症模型中，作者发现限制小鼠饮食中蛋氨酸的水平会抑制肿瘤生长。当与化疗药物5-氟尿嘧啶或放疗联合使用时，肿瘤生长也减少了。

在一项初步临床研究中，六名健康中年人接受了为期三周的低蛋氨酸饮食(相当于每日蛋氨酸摄入量减少83%)。作者发现，研究参与者的代谢物水平与相同饮食限制的小鼠的代谢物水平相关。他们提出，这些发现提供了特定饮食控制可能影响癌症结果的证据。

Abstract：

Nutrition exerts considerable effects on health, and dietary interventions are commonly used to treat diseases of metabolic aetiology. Although cancer has a substantial metabolic component1, the principles that define whether nutrition may be used to influence outcomes of cancer are unclear2. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. By contrast, whether specific dietary interventions can influence the metabolic pathways that are targeted in standard cancer therapies is not known. Here we show that dietary restriction of the essential amino acid methionine—the reduction of which has anti-ageing and anti-obesogenic properties—influences cancer outcome, through controlled and reproducible changes to one-carbon metabolism. This pathway metabolizes methionine and is the target of a variety of cancer interventions that involve chemotherapy and radiation. Methionine restriction produced therapeutic responses in two patient-derived xenograft models of chemotherapy-resistant RAS-driven colorectal cancer, and in a mouse model of autochthonous soft-tissue sarcoma driven by a G12D mutation in KRAS and knockout of p53 (KrasG12D/+;Trp53−/−) that is resistant to radiation. Metabolomics revealed that the therapeutic mechanisms operate via tumour-cell-autonomous effects on flux through one-carbon metabolism that affects redox and nucleotide metabolism—and thus interact with the antimetabolite or radiation intervention. In a controlled and tolerated feeding study in humans, methionine restriction resulted in effects on systemic metabolism that were similar to those obtained in mice. These findings provide evidence that a targeted dietary manipulation can specifically affect tumour-cell metabolism to mediate broad aspects of cancer outcome.

文章信息来自：https://www.nature.com/articles/s41586-019-1437-3

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