Regulation of TGF-β1-Induced EMT by Autophagy-Dependent Energy Metabolism in Cancer Cells

SIMPLE SUMMARY: The spread of cancer to other parts of the body is the primary cause of death in most patients. Autophagy is an intracellular maintenance process. Its role in initiating the spread of cancer is still debated. Here, we examined the connection between autophagy and the initial transition of lung cancer cells into the metastatic phenotype, capable of migrating to distant parts of the body. Repressing autophagy reduced the amount of the proteins responsible for this transition but not the expression of their corresponding genes. Therefore, autophagy may regulate the translation of these proteins. We further showed that autophagy involves in regulation of energy mediators, necessary for protein translation. Blocking autophagy and the resulting drop in energy levels diminishes the proteins necessary for initiating metastasis, which represents a potential target of cancer therapy. ABSTRACT: Metastasis is associated with poor prognosis and is the major cause of death in cancer patients. The epithelial to mesenchymal transition (EMT) is essential for cancer cells to acquire a highly migratory phenotype. Metabolic reprogramming is required to meet the energy demands during this process. Recent studies have indicated that autophagy is involved in EMT, during which cancer cells depend on autophagy activation for survival. However, accumulating evidence indicates that autophagy’s involvement in cancer is context-dependent, acting as either promoter or inhibitor. In this study, we investigated the role of autophagy in supplying energy to support EMT. We induced EMT in Non-small cell lung cancer A549 cells using TGF- [Formula: see text] 1 with and without autophagy inhibition. Suppression of autophagy activity by knocking down of BECN1 or chloroquine (CQ) treatment inhibited mesenchymal protein expression. Interestingly, TGF- [Formula: see text] 1 promoted the transcription of target mRNAs, SNAI1, VIM, and CDH2, regardless of autophagy status. The imbalance between protein and mRNA levels indicated the possibility of autophagy-dependent translational regulation. Since protein synthesis consumes large amounts of energy, it is tightly regulated via various cellular signaling pathways such as AMPK and mTOR. Our investigation showed inhibition of autophagy decreased ATP production from OXPHOS and led to the suppression of mRNA translation by phosphorylation of eukaryotic elongation factor 2 (eEF2). These results suggest that A549 non-small cell lung cancer required autophagy to maintain mitochondrial homeostasis during TGF- [Formula: see text] 1 induced EMT. In conclusion, blocking autophagy decreased energy production and down-regulated proteins synthesis inhibiting TGF- [Formula: see text] 1 induced EMT.