Abstract
Increased glucose uptake is a known hallmark of cancer. Cancer cells need glucose for energy production via glycolysis and the tricarboxylic acid cycle, and also to fuel the pentose phosphate pathway, the serine biosynthetic pathway, lipogenesis, and the hexosamine pathway. For this reason, glucose transport inhibition is an emerging new treatment for different malignancies, including lung cancer. However, studies both in animal models and in humans have shown high levels of heterogeneity in the utilization of glucose and other metabolites in cancer, unveiling a complexity that is difficult to target therapeutically. Here, we present an overview of different levels of heterogeneity in glucose uptake and utilization in lung cancer, with diagnostic and therapeutic implications.
Highlights
Increased glucose uptake is a hallmark of cancer
Increased glucose uptake and slowed mitochondrial utilization of glucose in rapidly proliferating tissues provides a fast source of energy through ATP, and feeds a number of anabolic pathways that are required for buildup of biomass, including the pentose phosphate pathway, the serine biosynthetic pathway, the hexosamine biosynthetic pathway, and lipid biosynthesis
The pentose phosphate pathway is an alternative route of glucose utilization that results in the production of NADPH, ribose, and glycolytic intermediates [26]
Summary
Increased glucose uptake is a hallmark of cancer. The increased metabolic requirements of neoplastic cells have been extensively studied, and therapeutic strategies are being investigated to hinder tumor growth by interfering with glucose uptake and metabolism in cancer cells [1,2,3,4,5]. In the hexosamine biosynthetic pathway, an aminotransferase reaction commits fructose-6-phosphate from glycolysis to the production of N-acetyl-glucosamine for glycosylation reactions This pathway has been described as a sensor of nutrient availability that stimulates cancer cell growth and proliferation when the abundance of glucose and other nutrients in the microenvironment allow it [32]. The increased glycolysis and the reduced utilization of pyruvate in the mitochondria create a bottleneck effect enriching the cells of metabolites required for the described branching anabolic and redox pathways This effect is achieved in many cancers by upregulation of the fetal isoform of pyruvate kinase, M2, which has slower and more regulated activity than the adult isoform M1, slowing down the last step of glycolysis [39].
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