Abstract
The zinc finger transcription factor Snail is a known effector of epithelial-to-mesenchymal transition (EMT), a process that underlies the enhanced invasiveness and chemoresistance of common to cancerous cells. Induction of Snail-driven EMT has also been shown to drive a range of pro-survival metabolic adaptations in different cancers. In the present study, we sought to determine the specific role that Snail has in driving EMT and adaptive metabolic programming in pancreatic ductal adenocarcinoma (PDAC) by overexpressing Snail in a PDAC cell line, Panc1, and in immortalized, non-tumorigenic human pancreatic ductal epithelial (HPDE) cells. Snail overexpression was able to induce EMT in both pancreatic cell lines through suppression of epithelial markers and upregulation of mesenchymal markers alongside changes in cell morphology and enhanced migratory capacity. Snail-overexpressed pancreatic cells additionally displayed increased glucose uptake and lactate production with concomitant reduction in oxidative metabolism measurements. Snail overexpression reduced maximal respiration in both Panc1 and HPDE cells, with further reductions seen in ATP production, spare respiratory capacity and non-mitochondrial respiration in Snail overexpressing Panc1 cells. Accordingly, lower expression of mitochondrial electron transport chain proteins was observed with Snail overexpression, particularly within Panc1 cells. Modelling of 13C metabolite flux within both cell lines revealed decreased carbon flux from glucose in the TCA cycle in snai1-overexpressing Panc1 cells only. This work further highlights the role that Snail plays in EMT and demonstrates its specific effects on metabolic reprogramming of glucose metabolism in PDAC.
Highlights
Originating from the ductal cells of exocrine pancreas, pancreatic ductal adenocarcinoma (PDAC) is arguably the most lethal type of common cancer, and its dismal prognosis has remained relatively unchanged over the past three decades [1,2]
We have previously shown augmentations of glucose consumption and lactate output in Panc1 cells undergoing tumor necrosis factor-α (TNFα)- and transformation growth factor-β (TGFβ)-induced epithelial-to-mesenchymal transition (EMT), with differential molecular changes observed in the two models [41]
Snail overexpression in the PDAC cell line Panc1 and in non-tumorigenic human pancreatic ductal epithelial (HPDE) cells resulted in the induction of EMT and a range of accompanying metabolic changes
Summary
Originating from the ductal cells of exocrine pancreas, pancreatic ductal adenocarcinoma (PDAC) is arguably the most lethal type of common cancer, and its dismal prognosis has remained relatively unchanged over the past three decades [1,2]. Metastatic PDAC cell sublines have been reported to possess EMT-like phenotype and Snail upregulation when compared with the bulk of tumor cells [12]. Such observations are confirmed by studies using cultured cells where Snail overexpression in Panc, AsPC-1 and BxPC-3 cells led to overt EMT with alterations in morphology and gene expression and increased transwell invasion capacity [13,14,15]. The process of EMT involves major changes to the gene expression network and cellular phenotype It is, likely to be accompanied by metabolic alterations to accommodate the shift in cell’s priority from proliferation to invasion of neighboring tissues and to adapt to changes in the environment. Med. 2019, 8, 822 report that EMT in both cell lines is associated with elevated glucose uptake and lactate excretion, as well as downregulation of proteins in the mitochondrial electron transport chain (ETC)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
