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

机译：膳食蛋氨酸影响小鼠癌症模型的治疗，并改变人类新陈代谢

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摘要

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.
机译：营养对健康产生相当大的影响，饮食干预常常用于治疗代谢性病学的疾病。虽然癌症具有大量代谢组分（1），但定义营养是否可用于影响癌症的结果的原则尚不清楚（2）。然而，建立靶向药理学药物或辐射的代谢途径有时会导致受控治疗结果。相比之下，特定的膳食干预是否可以影响标准癌症疗法中靶向的代谢途径是未知的。在这里，我们表明，通过对单碳代谢的受控和可重复的变化，对基本氨基酸蛋氨酸的膳食限制 - 降低抗衰老和抗噬菌性的性能影响癌症结果。该途径代谢甲硫氨酸，是涉及化疗和辐射的各种癌症干预的靶标。甲硫氨酸限制在两种患者衍生的抗性RAS-驱动结直肠癌中产生的治疗反应，以及在P53（KRAS（G12D / +）的G12D突变驱动的Autophonoons软组织肉瘤的小鼠模型中（KRAS（G12D / + ）; TRP53（ - / - ））耐辐射。代谢组学显示，治疗机制通过肿瘤 - 细胞 - 自主效应通过一种碳代谢来通过影响氧化还原和核苷酸代谢 - 因此与抗体atabolite或辐射干预相互作用。在人类的受控和耐受的饲养研究中，甲硫氨酸限制导致对与小鼠中获得的那些类似的系统代谢产生影响。这些发现提供了证据表明有针对性的膳食操纵可以特别影响肿瘤细胞代谢以介导癌症结果的广泛方面。

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  • 来源
    《Nature》 |2019年第7769期|397-401|共5页
  • 作者

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

  • 作者单位

    Duke Univ Sch Med Dept Pharmacol & Canc Biol Durham NC 27708 USA;

    Duke Univ Sch Med Dept Pharmacol & Canc Biol Durham NC 27708 USA;

    Duke Univ Sch Med Dept Pharmacol & Canc Biol Durham NC 27708 USA;

    Duke Univ Sch Med Dept Pharmacol & Canc Biol Durham NC 27708 USA;

    Duke Univ Med Ctr Dept Radiat Oncol Durham NC USA;

    Duke Univ Ctr Genom & Computat Biol Durham NC USA|Duke Univ Med Ctr Dept Med Oncol Durham NC USA;

    Penn State Univ Coll Med Dept Publ Hlth Sci Hershey PA USA;

    Penn State Univ Clin Res Ctr State Coll PA USA;

    Penn State Univ Coll Med Dept Publ Hlth Sci Hershey PA USA;

    Duke Univ Sch Med Dept Pharmacol & Canc Biol Durham NC 27708 USA;

    Duke Univ Sch Med Dept Pharmacol & Canc Biol Durham NC 27708 USA;

    Duke Univ Sch Med Dept Pharmacol & Canc Biol Durham NC 27708 USA;

    Duke Univ Sch Med Dept Pharmacol & Canc Biol Durham NC 27708 USA|Duke Univ Med Ctr Dept Radiat Oncol Durham NC USA;

    Duke Univ Ctr Genom & Computat Biol Durham NC USA|Duke Univ Med Ctr Dept Med Oncol Durham NC USA;

    Orentreich Fdn Adv Sci Cold Spring on Hudson NY USA;

    Duke Univ Sch Med Dept Pharmacol & Canc Biol Durham NC 27708 USA;

  • 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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