LACTB is a tumour suppressor that modulates lipid metabolism and cell state.
LACTB is a tumour suppressor that modulates lipid metabolism and cell state.
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DOI：
10.1038/nature21408
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发表时间：
2017-03-30
期刊：
影响因子：
64.8
通讯作者：
Weinberg RA
中科院分区：
文献类型：
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作者：
Keckesova Z;Donaher JL;De Cock J;Freinkman E;Lingrell S;Bachovchin DA;Bierie B;Tischler V;Noske A;Okondo MC;Reinhardt F;Thiru P;Golub TR;Vance JE;Weinberg RA
有丝分裂后的分化细胞表现出与活跃生长的肿瘤细胞不同的多种特征，例如细胞周期抑制剂和分化因子的表达。我们假设这些分化细胞的基因表达谱可以揭示可能充当肿瘤抑制因子的基因的身份。在这里，我们通过对小鼠和人类的体外和体内研究表明，线粒体蛋白 LACTB 可以有效抑制乳腺癌细胞的增殖。其作用机制涉及改变线粒体脂质代谢和乳腺癌细胞的分化。这至少部分是通过降低线粒体磷脂酰丝氨酸脱羧酶的水平来实现的，该酶参与线粒体磷脂酰乙醇胺的合成。这些观察发现了一种新型线粒体肿瘤抑制因子，并证明了线粒体脂质代谢与乳腺癌细胞分化程序之间的联系，从而揭示了以前未描述的肿瘤抑制机制。
Post-mitotic, differentiated cells exhibit a variety of characteristics that contrast with those of actively growing neoplastic cells, such as the expression of cell-cycle inhibitors and differentiation factors. We hypothesized that the gene expression profiles of these differentiated cells could reveal the identities of genes that may function as tumour suppressors. Here we show, using in vitro and in vivo studies in mice and humans, that the mitochondrial protein LACTB potently inhibits the proliferation of breast cancer cells. Its mechanism of action involves alteration of mitochondrial lipid metabolism and differentiation of breast cancer cells. This is achieved, at least in part, through reduction of the levels of mitochondrial phosphatidylserine decarboxylase, which is involved in the synthesis of mitochondrial phosphatidylethanolamine. These observations uncover a novel mitochondrial tumour suppressor and demonstrate a connection between mitochondrial lipid metabolism and the differentiation program of breast cancer cells, thereby revealing a previously undescribed mechanism of tumour suppression.