Abstract
Epithelial–mesenchymal transition (EMT)—a fundamental process in embryogenesis and wound healing—promotes tumor metastasis and resistance to chemotherapy. While studies have identified signaling components and transcriptional factors responsible in the TGF-β-dependent EMT, whether and how intracellular metabolism is integrated with EMT remains to be fully elucidated. Here, we showed that TGF-β induces reprogramming of intracellular amino acid metabolism, which is necessary to promote EMT in non-small cell lung cancer cells. Combined metabolome and transcriptome analysis identified prolyl 4-hydroxylase α3 (P4HA3), an enzyme implicated in cancer metabolism, to be upregulated during TGF-β stimulation. Further, knockdown of P4HA3 diminished TGF-β-dependent changes in amino acids, EMT, and tumor metastasis. Conversely, manipulation of extracellular amino acids induced EMT-like responses without TGF-β stimulation. These results suggest a previously unappreciated requirement for the reprogramming of amino acid metabolism via P4HA3 for TGF-β-dependent EMT and implicate a P4HA3 inhibitor as a potential therapeutic agent for cancer.
Highlights
Epithelial–mesenchymal transition (EMT)—a fundamental process in embryogenesis and wound healing—promotes tumor metastasis and resistance to chemotherapy
To investigate the effect of Transforming growth factor-β (TGF-β)-induced EMT on metabolism in nonsmall-cell lung cancer (NSCLC) cells, three well-studied NSCLC cell lines (A549, HCC827, and H358) were treated with TGF-β for 3 days as well as several weeks, and polar metabolites were quantified by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS)[24] (Supplementary Data 1–3)
TGF-β-induced EMT of NSCLC cells was verified by the morphological changes and expression of EMT marker genes E-cadherin (CDH1), N-cadherin (CDH2), fibronectin 1 (FN1), matrix metallopeptidase (MMP)-9, and MMP-2 (Supplementary Figs. 1a–f)
Summary
Epithelial–mesenchymal transition (EMT)—a fundamental process in embryogenesis and wound healing—promotes tumor metastasis and resistance to chemotherapy. We showed that TGF-β induces reprogramming of intracellular amino acid metabolism, which is necessary to promote EMT in non-small cell lung cancer cells. 1234567890():,; Epithelial–mesenchymal transition (EMT) is a reversible differentiation process during which epithelial cells acquire mesenchymal properties It is characterized by the loss of cell–cell adhesion and conversion from a cobblestone-like to more spindle-shaped morphology, enhancing cell motility and invasion. Recent studies have reported that the loss of fumarate hydratase and subsequent accumulation of fumarate in renal cancer cells[21], as well as the increase in asparagine bioavailability via asparagine synthetase in metastatic breast cancer[22], and the increased expression of dihydropyrimidine dehydrogenase leading to dihydropyrimidine production in breast cancer cells[23] contributes to the acquisition of mesenchymal characteristics in vitro and in vivo These findings suggest that the bioavailability of certain metabolites is critical for inducing EMT. In the current study, we identified the reprogramming of amino acid metabolism during TGF-β-induced EMT through a comprehensive metabolic analysis and demonstrated its significance to EMT phenotypes
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