Baumann Jan, Kokabee Mostafa, Wong Jason, Balasubramaniyam Rakshika, Sun Yan, Conklin Douglas S
Cancer Research Center, Department of Biomedical Sciences, State University of New York, University at Albany, Rensselaer, NY 12144, USA.
Oncotarget. 2018 Jun 5;9(43):27133-27150. doi: 10.18632/oncotarget.25500.
Recent work has shown that HER2/neu-positive breast cancer cells rely on a unique Warburg-like metabolism for survival and aggressive behavior. These cells are dependent on fatty acid (FA) synthesis, show markedly increased levels of stored fats and disruption of the synthetic process results in apoptosis. In this study, we used global metabolite profiling and a multi-omics network analysis approach to model the metabolic changes in this physiology under palmitate-supplemented growth conditions to gain insights into the molecular mechanism and its relevance to disease prevention and treatment. Computational analyses were used to define pathway enrichment based on the dataset of significantly altered metabolites and to integrate metabolomics and transcriptomics data in a multi-omics network analysis. Network-predicted changes and functional relationships were tested with cell assays . Palmitate-supplemented growth conditions induce distinct metabolic alterations. Growth of HER2-normal MCF7 cells is unaffected under these conditions whereas HER2/neu-positive cells display unchanged neutral lipid content, AMPK activation, inhibition of fatty acid synthesis and significantly altered glutamine, glucose and serine/glycine metabolism. The predominant upregulated lipid species is the novel bioactive lipid N-palmitoylglycine, which is non-toxic to these cells. Limiting the availability of glutamine significantly ameliorates the lipotoxic effects of palmitate, reduces CHOP and XBP1(s) induction and restores the expression levels of HER2 and HER3. The study shows that HER2/neu-positive breast cancer cells change their metabolic phenotype in the presence of palmitate. Palmitate induces AMPK activation and inhibition of fatty acid synthesis that feeds back into glycolysis as well as anaplerotic glutamine metabolism.
近期研究表明，HER2/neu阳性乳腺癌细胞依靠独特的类瓦伯格代谢来维持生存和侵袭性行为。这些细胞依赖脂肪酸（FA）合成，储存脂肪水平显著升高，合成过程的破坏会导致细胞凋亡。在本研究中，我们使用全局代谢物谱分析和多组学网络分析方法，对在添加棕榈酸的生长条件下该生理过程中的代谢变化进行建模，以深入了解分子机制及其与疾病预防和治疗的相关性。通过计算分析基于显著改变的代谢物数据集定义通路富集，并在多组学网络分析中整合代谢组学和转录组学数据。利用细胞实验对网络预测的变化和功能关系进行测试。添加棕榈酸的生长条件会诱导明显的代谢改变。在这些条件下，HER2正常的MCF7细胞的生长不受影响，而HER2/neu阳性细胞的中性脂质含量、AMPK激活、脂肪酸合成抑制均未改变，但谷氨酰胺、葡萄糖和丝氨酸/甘氨酸代谢显著改变。主要上调的脂质种类是新型生物活性脂质N-棕榈酰甘氨酸，它对这些细胞无毒。限制谷氨酰胺的可用性可显著改善棕榈酸的脂毒性作用，降低CHOP和XBP1(s)的诱导，并恢复HER2和HER3的表达水平。该研究表明，HER2/neu阳性乳腺癌细胞在棕榈酸存在下会改变其代谢表型。棕榈酸诱导AMPK激活和脂肪酸合成抑制，这会反馈到糖酵解以及回补性谷氨酰胺代谢中。
