研究:降低飲食中絲氨酸的含量可阻礙腫瘤生長
美國加州大學(xué)圣地亞哥分校Christian M. Metallo研究團隊發(fā)現(xiàn),絲氨酸缺乏通過改變鞘脂多樣性限制腫瘤生長。相關(guān)論文在線發(fā)表在2020年8月12日出版的《自然》雜志上。
研究人員利用氨基酸代謝和絲氨酸棕櫚酰轉(zhuǎn)移酶(SPT)的混雜來調(diào)節(jié)內(nèi)源有毒性脫氧鞘脂的合成和減緩腫瘤進展。錨定非依賴性生長重編程了包含絲氨酸、丙氨酸和丙酮酸的代謝網(wǎng)絡(luò),從而導(dǎo)致脫氧鞘脂的內(nèi)源合成和積累。靶向線粒體丙酮酸載體可促進丙氨酸氧化,以減輕脫氧鞘脂的合成并改善球狀體的生長,這類似于直接抑制SPT或神經(jīng)酰胺合成的表型。限制飲食中的絲氨酸和甘氨酸有效誘導(dǎo)了脫氧鞘糖脂的積累,同時降低了小鼠異種移植模型中腫瘤的生長。
藥物抑制SPT可恢復(fù)飲食缺乏絲氨酸和甘氨酸小鼠異種移植物的生長,通過抑制磷酸甘油酸脫氫酶(PHGDH)減少循環(huán)絲氨酸可導(dǎo)致脫氧鞘脂的積累并減緩腫瘤生長。因此,SPT將絲氨酸和線粒體丙氨酸代謝與膜脂質(zhì)多樣性聯(lián)系在一起,這進一步導(dǎo)致腫瘤對代謝壓力敏感。
據(jù)介紹,絲氨酸、甘氨酸和其他非必需氨基酸對于腫瘤進展至關(guān)重要,限制其可獲得性漸漸作為潛在的癌癥治療策略。然而,導(dǎo)致這種反應(yīng)的分子機制仍然不清楚,并且尚未有研究探索其對脂質(zhì)代謝的影響。當(dāng)使用丙氨酸作為底物時,SPT催化鞘脂從頭合成,但也會產(chǎn)生非典型的1-脫氧鞘脂。脫氧鞘脂類在SPTLC1或SPTLC2突變的情況下或在絲氨酸利用率較低情況下的聚集會引起神經(jīng)病變,并且已有研究報道脫氧鞘氨醇可作為抗癌藥。
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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