Hua Wan, Kostidis Sarantos, Mayboroda Oleg, Giera Martin, Hornsveld Marten, Ten Dijke Peter
Oncode Institute and Cell Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Institute of Rare Diseases, West China Hospital, Sichuan University, Chengdu 610041, China.
Metabolites. 2021 Sep 15;11(9):626. doi: 10.3390/metabo11090626.
The cytokine transforming growth factor-β (TGF-β) can induce normal breast epithelial cells to take on a mesenchymal phenotype, termed epithelial-to-mesenchymal transition (EMT). While the transcriptional and proteomic changes during TGF-β-induced EMT have been described, the metabolic rewiring that occurs in epithelial cells undergoing EMT is not well understood. Here, we quantitively analyzed the TGF-β-induced metabolic reprogramming during EMT of non-transformed NMuMG mouse mammary gland epithelial cells using nuclear magnetic resonance (NMR) spectroscopy. We found that TGF-β elevates glycolytic and tricarboxylic acid (TCA)-cycle activity and increases glutaminolysis. Additionally, TGF-β affects the hexosamine pathway, arginine-proline metabolism, the cellular redox state, and strongly affects choline metabolism during EMT. TGF-β was found to induce phosphocholine production. A kinase inhibitor RSM-93A that inhibits choline kinase α (CHKα) mitigated TGF-β-induced changes associated with EMT, i.e., increased filamentous (F)-actin stress fiber formation and N-Cadherin mesenchymal marker expression.
细胞因子转化生长因子-β（TGF-β）可诱导正常乳腺上皮细胞呈现间充质表型，即上皮-间充质转化（EMT）。虽然已描述了TGF-β诱导EMT过程中的转录和蛋白质组变化，但对经历EMT的上皮细胞中发生的代谢重编程了解不足。在此，我们使用核磁共振（NMR）光谱法定量分析了非转化的NMuMG小鼠乳腺上皮细胞EMT过程中TGF-β诱导的代谢重编程。我们发现，TGF-β提高了糖酵解和三羧酸（TCA）循环活性，并增加了谷氨酰胺分解代谢。此外，TGF-β影响己糖胺途径、精氨酸-脯氨酸代谢、细胞氧化还原状态，并在EMT过程中强烈影响胆碱代谢。发现TGF-β可诱导磷酸胆碱生成。抑制胆碱激酶α（CHKα）的激酶抑制剂RSM-93A减轻了TGF-β诱导的与EMT相关的变化，即丝状（F）-肌动蛋白应力纤维形成增加和N-钙黏蛋白间充质标志物表达增加。
