Dietary methionine influences therapy in mouse cancer models and alters human metabolism
Dietary methionine influences therapy in mouse cancer models and alters human metabolism
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DOI：
10.1038/s41586-019-1437-3
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发表时间：
2019-08-15
期刊：
影响因子：
64.8
通讯作者：
Locasale, Jason W.
中科院分区：
文献类型：
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作者：
Gao, Xia;Sanderson, Sydney M.;Locasale, Jason W.
营养对健康有相当大的影响，饮食干预通常用于治疗代谢病因疾病。虽然癌症有大量的代谢成分（1），但定义营养是否可以用来影响癌症结果的原则尚不清楚（2）。然而，已经确定，用药理学试剂或辐射靶向代谢途径有时可以导致受控的治疗结果。相比之下，特定的饮食干预是否会影响标准癌症治疗中靶向的代谢途径尚不清楚。在这里，我们表明，饮食限制的必需氨基酸甲硫氨酸减少具有抗衰老和抗肥胖的特性，影响癌症的结果，通过控制和可重复的变化，以一碳代谢。该途径代谢甲硫氨酸，并且是涉及化疗和放疗的各种癌症干预的靶点。在两种化疗耐药RAS驱动的结直肠癌患者来源的异种移植模型中，以及在由KRAS中的G12 D突变和对辐射耐药的p53（Kras（G12 D/+）; Trp 53（-/-））敲除驱动的自体软组织肉瘤的小鼠模型中，甲硫氨酸限制产生了治疗反应。代谢组学揭示，治疗机制是通过肿瘤细胞的自主作用，通过影响氧化还原和核苷酸代谢的一碳代谢，从而与抗代谢药或放射干预相互作用。在一项人体对照和耐受性喂养研究中，蛋氨酸限制对全身代谢的影响与小鼠中获得的结果相似。这些发现提供了证据，表明有针对性的饮食控制可以特异性地影响肿瘤细胞代谢，从而介导癌症结果的广泛方面。
Nutrition exerts considerable effects on health, and dietary interventions are commonly used to treat diseases of metabolic aetiology. Although cancer has a substantial metabolic component(1), the principles that define whether nutrition may be used to influence outcomes of cancer are unclear(2). 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 (Kras(G12D/+); 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.