The role of 6-phosphofurocto-2-kinase / fructose-2,6-bisphosphatase enzymes in epithelial-mesenchymal transition induced by transforming growth factor β-1

Transforming growth factor-beta (TGFβ) is a potent activator of Epithelial-mesenchymal transition (EMT) that is essential for the acquisition of malignant properties in tumor cells. Although recent studies suggest that the EMT in tumor cells is associated with reprogramming energy metabolism and TGFβ has been shown to stimulate glycolysis in multiple primary cell lines, little is known about TGFβ's effect on glucose metabolism. The 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) enzyme family comprises of bifunctional enzymes that control the levels of fructose-2,6-bisphosphate (F2,6BP), a potent allosteric activator of phosphofructokinase-1 (PFK-1). We found that, for the first time, TGFβ increases glycolysis in the pancreatic cancer cell line Panc1 by inducing PFKFB3 expression and that PFKFB3 is required for TGFβ mediated invasion of Panc1 cells in vitro. Furthermore, we demonstrated that the effect of TGFβ on Snail induction is largely reduced by PFKFB3 silencing. These findings suggest that PFKFB3 is involved in the regulation of Snail and acquisition of an invasive and glycolytic phenotype by TGFβ in Panc1 cells. In contrast with Panc1 cells, we showed that TGFβ-induced EMT reduces glycolysis in the lung cancer cell line A549. In addition, we determined that PFKFB4, whose expression increased with TGFβ, had no effect on the slowdown in glycolysis, but the mesenchymal phenotype observed in the A549 cell line with TGFβ decreased partially by suppression of PFKFB4. In conclusion these data suggest that PFKFB enzymes may have important roles in TGFβ-associated cellular processes and that different PFKFB isozymes that interact with TGFβ may contribute to distinct metabolic phenotypes in different tumor cells.