Figure 12. Reciprocal interactions between increased glucose uptake/metabolism and other signaling pathways.

Extracellular glucose is taken up by glucose transporters, including GLUT3, as well as by diffusion and is metabolized by hexokinase (HK) and glucose-6-phosphate isomerase (GPI) to enter different metabolic pathways. The glycolytic pathway includes subsequent steps mediated by PFK, ALDO, and GAPDH; LDH also supports the glycolytic pathway by production of the GAPDH coenzyme NAD+. These enzymes were all upregulated in T4-2 cells, leading to loss of integration of form and function. The sAC-EPAC-RAP1 pathway regulates β1 integrin positively, most likely via a direct link between ATP production in the glycolytic pathway and cAMP generation by sAC, which is mediated by tumor-specific PKM2-sAC association. HBP (dashed outline) is rate-limited by GFPT, which is also upregulated via activation of oncogenic signaling. Downstream O-GlcNAcylation of target proteins mediated by OGT regulates β1 integrin, EGFR, and GLUT3 expression. Inhibition of any of the key metabolic enzymes or the key signaling molecules results in suppression of all the others, reestablishment of the polarized acinar structure, and growth arrest. See Results and Discussion for details. Fonts distinguish metabolites (italic), proteins (bold), and genes (bold and italic). Colored text highlights proteins upregulated in T4-2 cells (orange), energy carrier molecules (green), and chemical reagents that do (red) or do not (purple) induce phenotypic reversion. 2DGP, 2DG-phosphate; G6P, glucose-6-phosphate; F1,6BP, fructiose-1,6-bisphosphate; GAD3P, glyceraldehyde-3-phosphate; DHAP, dihydroxyacetone phosphate; 1,3BPG, 1,3-bisphosphoglycerate; GlcNAc, N-acetylglucosamine.