Metabolic Reprogramming of Mammary Epithelial Cells during TGF-β-Induced Epithelial-to-Mesenchymal Transition

The cytokine transforming growth factor-beta (TGF-beta) 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-beta-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-beta-induced metabolic reprogramming during EMT of non-transformed NMuMG mouse mammary gland epithelial cells using nuclear magnetic resonance (NMR) spectroscopy. We found that TGF-beta elevates glycolytic and tricarboxylic acid (TCA)-cycle activity and increases glutaminolysis. Additionally, TGF-beta affects the hexosamine pathway, arginine-proline metabolism, the cellular redox state, and strongly affects choline metabolism during EMT. TGF-beta was found to induce phosphocholine production. A kinase inhibitor RSM-93A that inhibits choline kinase alpha (CHK alpha) mitigated TGF-beta-induced changes associated with EMT, i.e., increased filamentous (F)-actin stress fiber formation and N-Cadherin mesenchymal marker expression.

Automated summary

TGF-beta induces metabolic reprogramming in epithelial cells during EMT, affecting glycolysis, TCA cycle, glutaminolysis, choline metabolism, cellular redox state, and other pathways. Inhibiting choline kinase alpha with a kinase inhibitor can attenuate TGF-beta-induced changes associated with EMT.