Modulating the therapeutic response of tumours to dietary serine and glycine starvation
Modulating the therapeutic response of tumours to dietary serine and glycine starvation
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DOI：
10.1038/nature22056
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发表时间：
2017-04-20
期刊：
影响因子：
64.8
通讯作者：
Vousden, Karen H.
中科院分区：
文献类型：
--
作者：
Maddocks, Oliver D. K.;Athineos, Dimitris;Vousden, Karen H.
非必需氨基酸丝氨酸和甘氨酸在多种支持癌细胞生长和增殖的合成代谢过程中被使用（参考文献1）。虽然一些癌细胞上调从头合成丝氨酸（2-4），但许多其他癌细胞依赖外源丝氨酸来实现最佳生长（5-7）。在异种和同种异体移植模型中，限制饮食中的丝氨酸和甘氨酸可以减少肿瘤的生长（7,8）。本研究表明，在基因工程小鼠肠癌（由Apc失活驱动）或淋巴瘤（由Myc激活驱动）模型中，这一观察结果转化为更具临床相关性的本地肿瘤。在这些模型中，限制饮食中摄入丝氨酸和甘氨酸后，通过拮抗抗氧化反应进一步提高了存活率。线粒体氧化磷酸化的破坏（使用双胍类）导致复杂的反应，可以改善或阻碍丝氨酸和甘氨酸饥饿的抗肿瘤作用。值得注意的是，Kras驱动的胰腺癌和肠癌小鼠模型对丝氨酸和甘氨酸的消耗反应较弱，这反映了激活的Kras能够增加丝氨酸合成途径中部分酶的表达，从而促进从头合成丝氨酸。
The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis(2-4), many others rely on exogenous serine for optimal growth(5-7). Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models(7,8). Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.