美国杜克大学医学院Jason W. Locasale牵头的美国联合研究团队取得新进展。他们的最新研究探明了膳食蛋氨酸影响小鼠癌症模型中的治疗、并改变人体新陈代谢。相关论文发表在2019年8月15日出版的《自然》上。

研究团队通过控制和可复制的单碳代谢变化，证明了饮食限制必需氨基酸甲硫氨酸（俗称蛋氨酸）减少具有抗衰老和抗致肥胖的特性，这会影响癌症的预后。该途径代谢蛋氨酸，是各种癌症干预的目标，包括化疗和放疗。蛋氨酸被限制在两种源自化疗的RAS驱动的结直肠癌患者来源的异种移植模型中，在一种小鼠自体软组织肉瘤模型中产生了治疗反应，这种肉瘤由KRAS中的G12D突变和对放疗耐药的p53敲除(Kras^G12D/+;Trp53^-/-)驱动。代谢组学揭示，治疗机制是通过肿瘤细胞对单碳代谢通量的自发影响起作用，具体是通过影响氧化还原和核苷酸代谢，从而与抗代谢物或辐射干预相互作用。在一项对人体进行控制和耐受的喂养研究中，蛋氨酸的限制导致了与小鼠相似的对全身代谢的影响。这些新发现提供了证据，均指向一个结论，即有针对性的饮食控制可以具体影响肿瘤细胞代谢，从而介导癌症结果的广泛方面。

据了解，营养对健康有重要影响，饮食干预常被用于治疗代谢病因学疾病。虽然癌症具有重要的代谢组分，但定义营养是否可用于影响癌症预后的原则尚不清楚。然而，目前已经证实，利用药物制剂或辐射靶向代谢途径有时可以导致控制的治疗结果。相比之下，特定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。

附：英文原文

Title: Dietary methionine influences therapy in mouse cancer models and alters human metabolism

Author: Xia Gao, Sydney M. Sanderson, Ziwei Dai, Michael A. Reid, Daniel E. Cooper, Min Lu, John P. Richie, Amy Ciccarella, Ana Calcagnotto, Peter G. Mikhael, Samantha J. Mentch, Juan Liu, Gene Ables, David G. Kirsch, David S. Hsu, Sailendra N. Nichenametla, Jason W. Locasale

Issue&Volume: Volume 572 Issue 7769

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 component, the principles that define whether nutrition may be used to influence outcomes of cancer are unclear. 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 methioninethe reduction of which has anti-ageing and anti-obesogenic propertiesinfluences 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 metabolismand 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.

DOI: 10.1038/s41586-019-1437-3

Source: https://www.nature.com/articles/s41586-019-1437-3