小柯机器人

美国加州大学圣地亚哥分校Christian M. Metallo研究团队发现，丝氨酸缺乏通过改变鞘脂多样性限制肿瘤生长。相关论文在线发表在2020年8月12日出版的《自然》杂志上。

研究人员利用氨基酸代谢和丝氨酸棕榈酰转移酶（SPT）的混杂来调节内源有毒性脱氧鞘脂的合成和减缓肿瘤进展。锚定非依赖性生长重编程了包含丝氨酸、丙氨酸和丙酮酸的代谢网络，从而导致脱氧鞘脂的内源合成和积累。靶向线粒体丙酮酸载体可促进丙氨酸氧化，以减轻脱氧鞘脂的合成并改善球状体的生长，这类似于直接抑制SPT或神经酰胺合成的表型。限制饮食中的丝氨酸和甘氨酸有效诱导了脱氧鞘糖脂的积累，同时降低了小鼠异种移植模型中肿瘤的生长。

药物抑制SPT可恢复饮食缺乏丝氨酸和甘氨酸小鼠异种移植物的生长，通过抑制磷酸甘油酸脱氢酶（PHGDH）减少循环丝氨酸可导致脱氧鞘脂的积累并减缓肿瘤生长。因此，SPT将丝氨酸和线粒体丙氨酸代谢与膜脂质多样性联系在一起，这进一步导致肿瘤对代谢压力敏感。

据介绍，丝氨酸、甘氨酸和其他非必需氨基酸对于肿瘤进展至关重要，限制其可获得性渐渐作为潜在的癌症治疗策略。然而，导致这种反应的分子机制仍然不清楚，并且尚未有研究探索其对脂质代谢的影响。当使用丙氨酸作为底物时，SPT催化鞘脂从头合成，但也会产生非典型的1-脱氧鞘脂。脱氧鞘脂类在SPTLC1或SPTLC2突变的情况下或在丝氨酸利用率较低情况下的聚集会引起神经病变，并且已有研究报道脱氧鞘氨醇可作为抗癌药。

附：英文原文

Title: Serine restriction alters sphingolipid diversity to constrain tumour growth

Author: Thangaselvam Muthusamy, Thekla Cordes, Michal K. Handzlik, Le You, Esther W. Lim, Jivani Gengatharan, Antonio F. M. Pinto, Mehmet G. Badur, Matthew J. Kolar, Martina Wallace, Alan Saghatelian, Christian M. Metallo

Issue&Volume: 2020-08-12

Abstract: Serine, glycine and other nonessential amino acids are critical for tumour progression, and strategies to limit their availability are emerging as potential therapies for cancer1,2,3. However, the molecular mechanisms driving this response remain unclear and the effects on lipid metabolism are relatively unexplored. Serine palmitoyltransferase (SPT) catalyses the de novo biosynthesis of sphingolipids but also produces noncanonical 1-deoxysphingolipids when using alanine as a substrate4,5. Deoxysphingolipids accumulate in the context of mutations in SPTLC1 or SPTLC26,7—or in conditions of low serine availability8,9—to drive neuropathy, and deoxysphinganine has previously been investigated as an anti-cancer agent10. Here we exploit amino acid metabolism and the promiscuity of SPT to modulate the endogenous synthesis of toxic deoxysphingolipids and slow tumour progression. Anchorage-independent growth reprogrammes a metabolic network involving serine, alanine and pyruvate that drives the endogenous synthesis and accumulation of deoxysphingolipids. Targeting the mitochondrial pyruvate carrier promotes alanine oxidation to mitigate deoxysphingolipid synthesis and improve spheroid growth, similar to phenotypes observed with the direct inhibition of SPT or ceramide synthesis. Restriction of dietary serine and glycine potently induces the accumulation of deoxysphingolipids while decreasing tumour growth in xenograft models in mice. Pharmacological inhibition of SPT rescues xenograft growth in mice fed diets restricted in serine and glycine, and the reduction of circulating serine by inhibition of phosphoglycerate dehydrogenase (PHGDH) leads to the accumulation of deoxysphingolipids and mitigates tumour growth. The promiscuity of SPT therefore links serine and mitochondrial alanine metabolism to membrane lipid diversity, which further sensitizes tumours to metabolic stress.

DOI: 10.1038/s41586-020-2609-x

Source: https://www.nature.com/articles/s41586-020-2609-x

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