Glucose Metabolism in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers, with a five-year survival rate of around 5% to 8%. To date, very few available drugs have been successfully used to treat PDAC due to the poor understanding of the tumor-specific features. One of the hallmarks of pancreatic cancer cells is the deregulated cellular energetics characterized by the “Warburg effect”. It has been known for decades that cancer cells have a dramatically increased glycolytic flux even in the presence of oxygen and normal mitochondrial function. Glycolytic flux is the central carbon metabolism process in all cells, which not only produces adenosine triphosphate (ATP) but also provides biomass for anabolic processes that support cell proliferation. Expression levels of glucose transporters and rate-limiting enzymes regulate the rate of glycolytic flux. Intermediates that branch out from glycolysis are responsible for redox homeostasis, glycosylation, and biosynthesis. Beyond enhanced glycolytic flux, pancreatic cancer cells activate nutrient salvage pathways, which includes autophagy and micropinocytosis, from which the generated sugars, amino acids, and fatty acids are used to buffer the stresses induced by nutrient deprivation. Further, PDAC is characterized by extensive metabolic crosstalk between tumor cells and cells in the tumor microenvironment (TME). In this review, we will give an overview on recent progresses made in understanding glucose metabolism-related deregulations in PDAC.

M2‑TAM subsets altered by lactic acid promote T‑cell apoptosis through the PD‑L1/PD‑1 pathway

“…The development and progression of a tumor depends not only on its proliferation, but also on its interactions with the local microenvironment (1). Tumors have hypoxic stress microenvironments (2). An acidic microenvironment [pH (6.5-6.8) vs. (7.4)] caused by a large amount of anaerobic glycolysis is an important characteristic of malignant tumors, and an important factor in inducing their occurrence, metastasis, and drug resistance (3).…”

Effect of Inhibition of GLUT1 Expression and Autophagy Modulation on the Growth and Migration of Laryngeal Carcinoma Stem Cells under Hypoxic and Low-Glucose Conditions

“…Autophagy modulates various metabolic pathways, including that centered on glucose [23]. Hypoxia and glucose deprivation may induce autophagy, promoting glucose uptake by upregulating GLUT-1 expression to increase the glycolytic ux and maintain nutrient uptake under stress conditions [21][22][23]40,41]. In airway progenitor cells, a lack of GLUT-1 impacts its recycling but not its expression, facilitating glucose uptake [40].…”

SWATH-MS based proteomic profiling of pancreatic ductal adenocarcinoma tumours reveals the interplay between the extracellular matrix and related intracellular pathways

“…Although GTR1 was downregulated, ENO3, a key glycolytic enzyme that reversible converts 2-phosphoglycerate to phosphoenolpyruvate, was overexpressed as observed in another study [87]. Increased glucose metabolism is characteristic of pancreatic cancer cells [88] and can be further regulated and exacerbated in hypoxic conditions [89,90]. Hypoxia has been linked to tumour stroma stiffness that is characteristic of the extracellular matrix of pancreatic tumours.…”