Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA.
West Coast Metabolomics Center, University of California, Davis, Davis, CA, USA; Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
J Lipid Res. 2021;62:100056. doi: 10.1016/j.jlr.2021.100056. Epub 2021 Feb 26.
Methionine (Met) is an essential amino acid and critical precursor to the cellular methyl donor S-adenosylmethionine. Unlike nontransformed cells, cancer cells have a unique metabolic requirement for Met and are unable to proliferate in growth media where Met is replaced with its metabolic precursor, homocysteine. This metabolic vulnerability is common among cancer cells regardless of tissue origin and is known as "methionine dependence", "methionine stress sensitivity", or the Hoffman effect. The response of lipids to Met stress, however, is not well-understood. Using mass spectroscopy, label-free vibrational microscopy, and next-generation sequencing, we characterize the response of lipids to Met stress in the triple-negative breast cancer cell line MDA-MB-468 and its Met stress insensitive derivative, MDA-MB-468res-R8. Lipidome analysis identified an immediate, global decrease in lipid abundances with the exception of triglycerides and an increase in lipid droplets in response to Met stress specifically in MDA-MB-468 cells. Furthermore, specific gene expression changes were observed as a secondary response to Met stress in MDA-MB-468, resulting in a downregulation of fatty acid metabolic genes and an upregulation of genes in the unfolded protein response pathway. We conclude that the extensive changes in lipid abundance during Met stress is a direct consequence of the modified metabolic profile previously described in Met stress-sensitive cells. The changes in lipid abundance likely results in changes in membrane composition inducing the unfolded protein response we observe.
蛋氨酸（Met）是一种必需氨基酸，也是细胞甲基供体 S-腺苷甲硫氨酸的关键前体。与非转化细胞不同，癌细胞对 Met 具有独特的代谢需求，并且无法在生长培养基中增殖，在该培养基中，Met 被其代谢前体同型半胱氨酸所取代。这种代谢脆弱性在癌症细胞中很常见，无论组织来源如何，都被称为“蛋氨酸依赖性”、“蛋氨酸应激敏感性”或霍夫曼效应。然而，脂质对 Met 应激的反应还不是很清楚。使用质谱、无标记振动显微镜和下一代测序，我们在三阴性乳腺癌细胞系 MDA-MB-468 及其 Met 应激不敏感衍生物 MDA-MB-468res-R8 中对脂质对 Met 应激的反应进行了表征。脂质组学分析发现，除了甘油三酯外，脂质丰度立即普遍下降，并对 Met 应激做出反应，具体表现为 MDA-MB-468 细胞中的脂质滴增加。此外，在 MDA-MB-468 中还观察到了特定基因表达的二次反应，导致脂肪酸代谢基因下调和未折叠蛋白反应途径基因上调。我们得出结论，在 Met 应激期间脂质丰度的广泛变化是 Met 应激敏感细胞中先前描述的代谢谱改变的直接结果。脂质丰度的变化可能导致膜组成的变化，从而诱导我们观察到的未折叠蛋白反应。
