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

Abstract

Metastasis is associated with poor prognosis and is the major cause of death in cancerpatients. The epithelial to mesenchymal transition (EMT) is essential for cancer cells to acquire ahighly migratory phenotype. Metabolic reprogramming is required to meet the energy demandsduring this process. Recent studies have indicated that autophagy is involved in EMT, during whichcancer cells depend on autophagy activation for survival. However, accumulating evidence indicatesthat 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 inducedEMT in Non-small cell lung cancer A549 cells using TGF-b1 with and without autophagy inhibition.Suppression of autophagy activity by knocking down of BECN1 or chloroquine (CQ) treatmentinhibited mesenchymal protein expression. Interestingly, TGF-b1 promoted the transcription oftarget mRNAs, SNAI1, VIM, and CDH2, regardless of autophagy status. The imbalance betweenprotein 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 cellularsignaling pathways such as AMPK and mTOR. Our investigation showed inhibition of autophagydecreased ATP production from OXPHOS and led to the suppression of mRNA translation byphosphorylation of eukaryotic elongation factor 2 (eEF2). These results suggest that A549 non-smallcell lung cancer required autophagy to maintain mitochondrial homeostasis during TGF-b1 inducedEMT. In conclusion, blocking autophagy decreased energy production and down-regulated proteinssynthesis inhibiting TGF-b1 induced EMT.Keywords: