Abstract
Lung cancer cells are well-documented to rewire their metabolism and energy production networks to support rapid survival and proliferation. This metabolic reorganization has been recognized as a hallmark of cancer. The increased uptake of glucose and the increased activity of the glycolytic pathway have been extensively described. However, over the past years, increasing evidence has shown that lung cancer cells also require glutamine to fulfill their metabolic needs. As a nitrogen source, glutamine contributes directly (or indirectly upon conversion to glutamate) to many anabolic processes in cancer, such as the biosynthesis of amino acids, nucleobases, and hexosamines. It plays also an important role in the redox homeostasis, and last but not least, upon conversion to α-ketoglutarate, glutamine is an energy and anaplerotic carbon source that replenishes tricarboxylic acid cycle intermediates. The latter is generally indicated as glutaminolysis. In this review, we explore the role of glutamine metabolism in lung cancer. Because lung cancer is the leading cause of cancer death with limited curative treatment options, we focus on the potential therapeutic approaches targeting the glutamine metabolism in cancer.
Highlights
Cancer cells exhibit metabolic alterations that distinguish them from healthy cells, which are recognized as one of the 10 hallmarks of cancer [1]
To compensate for the reduced influx of glucose-derived carbon towards acetyl-CoA and the permanent drain of TCA cycle intermediates into biosynthetic pathways, proliferating cancer cells increase their uptake of glutamine, a nonessential amino acid [15,16]
Two molecules of glutamine are consumed in the biosynthesis of the parent nucleotide inosine monophosphate (IMP) which is the precursor of adenosine monophosphate (AMP) and guanosine monophosphate (GMP)
Summary
Cancer cells exhibit metabolic alterations that distinguish them from healthy cells, which are recognized as one of the 10 hallmarks of cancer [1]. To compensate for the reduced influx of glucose-derived carbon towards acetyl-CoA and the permanent drain of TCA cycle intermediates into biosynthetic pathways, proliferating cancer cells increase their uptake of glutamine, a nonessential amino acid [15,16]. In marked contrast to normal cells, lung cancer cells become addicted to glutamine as a consequence of aberrantly activated oncogenes, and the loss of tumor suppressors [17]. These alterations do result in the import of glutamine via the upregulation of glutamine transporters, but they promote the expression of metabolic enzymes involved in the metabolism of glutamine [18]. The efflux of glutamine, coupled to the import of essential amino acids such as leucine, results in the activation of the mammalian target of rapamycin (mTOR) pathway, which promotes the synthesis of proteins and inhibits autophagy [17]
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