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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies, which is projected to soon become the second leading cause of cancer-related deaths in the US [1].Oncogenic Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutations, which occur in over90% of human PDAC, are the dominant driver for tumor progression and play a critical role in reprogramming metabolism [2]
mannose phosphate isomerase (MPI) catalyzes the conversion between fructose-6-phosphate and mannose-6-phosphate and high dose mannose treatment in MPI-low cells leads to the accumulation of mannose-6-phosphate, which in turn shuts down glycolysis and suppresses tumor growth through the feedback inhibition of glycolytic enzymes hexokinase (HK) and phosphoglucose isomerase (PGI) [37,38]
It has recently been shown that, compared to proliferating tumor cells, PDAC tumor-initiating cells (TICs) are equipped with limited metabolic plasticity and exhibit decreased glycolysis activity accompanied with enhanced mitochondrial oxidative phosphorylation (OXPHOS) [99,100]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies, which is projected to soon become the second leading cause of cancer-related deaths in the US [1]. Branched metabolism pathways have proven to work together individually to KRAS mutation in can enhance the glycolytic pathway by upregulating the expression promote tumorigenesis. The enhanced biomass support (PPP and serine biosynthesis pathway), reactive oxygen species (ROS) maintenance glucose metabolism metabolism can promote. Oncogenic KRAS reprograms the glutamine metabolism maintenance (glutamine metabolism and TCA cycle), signal modulation (HBP), and DNA to support the redox homeostasis of PDAC [5]. Lipogenic tumors are associated with the epithelial phenotype, whereas metabolite profiling analysis characterized three different metabolic subtypes of PDAC, including the glycolytic subtype was relatedand to the mesenchymal phenotype. Accumulating evidence has established that the metabolic reprogramming in the tumor environment from isstromal cells can be taken up by cancer cells to support tumor growth or may be used to generate critical for PDAC tumorigenesis.
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