Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.

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Regulation of cancer cell metabolism

The biology of cancer: metabolic reprogramming fuels cell growth and proliferation

▪ Abstract Most prokaryotic signal-transduction systems and a few eukaryotic pathways use phosphotransfer schemes involving two conserved components, a histidine protein kinase and a response regul...

Two-component signal transduction

Warburg's observation that cancer cells exhibit a high rate of glycolysis even in the presence of oxygen (aerobic glycolysis) sparked debate over the role of glycolysis in normal and cancer cells. Although it has been established that defects in mitochondrial respiration are not the cause of cancer or aerobic glycolysis, the advantages of enhanced glycolysis in cancer remain controversial. Many cells ranging from microbes to lymphocytes use aerobic glycolysis during rapid proliferation, which suggests it may play a fundamental role in supporting cell growth. Here, we review how glycolysis contributes to the metabolic processes of dividing cells. We provide a detailed accounting of the biosynthetic requirements to construct a new cell and illustrate the importance of glycolysis in providing carbons to generate biomass. We argue that the major function of aerobic glycolysis is to maintain high levels of glycolytic intermediates to support anabolic reactions in cells, thus providing an explanation for why in...

/pdf/aerobic-glycolysis-meeting-the-metabolic-requirements-of-3fer2kszx4.pdf

Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation

Tumor cell proliferation requires rapid synthesis of macromolecules including lipids, proteins, and nucleotides. Many tumor cells exhibit rapid glucose consumption, with most of the glucose-derived carbon being secreted as lactate despite abundant oxygen availability (the Warburg effect). Here, we used 13C NMR spectroscopy to examine the metabolism of glioblastoma cells exhibiting aerobic glycolysis. In these cells, the tricarboxylic acid (TCA) cycle was active but was characterized by an efflux of substrates for use in biosynthetic pathways, particularly fatty acid synthesis. The success of this synthetic activity depends on activation of pathways to generate reductive power (NADPH) and to restore oxaloacetate for continued TCA cycle function (anaplerosis). Surprisingly, both these needs were met by a high rate of glutamine metabolism. First, conversion of glutamine to lactate (glutaminolysis) was rapid enough to produce sufficient NADPH to support fatty acid synthesis. Second, despite substantial mitochondrial pyruvate metabolism, pyruvate carboxylation was suppressed, and anaplerotic oxaloacetate was derived from glutamine. Glutamine catabolism was accompanied by secretion of alanine and ammonia, such that most of the amino groups from glutamine were lost from the cell rather than incorporated into other molecules. These data demonstrate that transformed cells exhibit a high rate of glutamine consumption that cannot be explained by the nitrogen demand imposed by nucleotide synthesis or maintenance of nonessential amino acid pools. Rather, glutamine metabolism provides a carbon source that facilitates the cell's ability to use glucose-derived carbon and TCA cycle intermediates as biosynthetic precursors.

https://www.pnas.org/content/pnas/104/49/19345.full.pdf

Beyond aerobic glycolysis : Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis

Mp02-04 invasion and assessment of intracellular bacterial colony (ibc) formation in uroepithelial cells by uropathogenic e. coli (upec) of different phylogenetic groups suggest alternate entry mechanisms

Facile transduction with P1 phage in Escherichia coli associated with urinary tract infections.

Mp02-01 comparative transcriptomics suggests convergent and divergent properties of uropathogenic escherichia coli

The expression of glnA (ammonia-assimilating glutamine synthetase) is high for uropathogenic E. coli grown in urine. Because glnA is part of an operon that codes for regulators of the nitrogen-regulated (Ntr) response, high glnA expression has been interpreted to suggest nitrogen limitation, which is unexpected because of the high urinary ammonia concentration and the extremely rapid bacterial growth. We present evidence that glnA expression does not result from nitrogen limitation. First, in the presence of ammonia, urea induced expression of glnA from the cAMP receptor protein (Crp)- dependent glnAp1 promoter, which circumvents control from the nitrogen-regulated glnAp2 promoter. This urea effect on glnA expression has not been previously described. Second, the most abundant amino acids in urine inhibited GS activity, based on reversal of the inhibition by glutamate and glutamine, and increased glnA expression. The relevance of these inhibitory amino acids in natural environments has not been previously demonstrated. Third, neither urea nor the inhibitory amino acids induced other Ntr genes, i.e., high glnA expression can be independent of other Ntr genes. Finally, the urea-dependent induction did not result in GlnA synthesis because of a previously undescribed translational control. We conclude that glnA expression in urea-containing environments does not imply growth rate-limiting nitrogen restriction and is consistent with rapid growth of uropathogenic E. coli. Significance Urinary tract infections (UTIs), often caused by E. coli, frequently become resistant to antibiotic treatment. Expressed metabolic genes during an infection could guide development of urgently-needed alternate or adjunct therapies. glnA (glutamine synthetase) is expressed during growth in urine, which implies growth-restricting nitrogen limitation. We show that glnA expression results from urinary amino acids that inhibit GlnA activity and urea, but not from nitrogen limitation. Urinary components will vary greatly between individuals which suggests corresponding variations in glnA expression. GlnA may be a metabolic vulnerability during UTIs, which may depend on a variable urinary composition. glnA expression may be important in a complex host-pathogen interaction, but may not be a good therapeutic target.

Nitrogen-limitation independent control of glnA (glutamine synthetase) expression in Escherichia coli by urea, several amino acids, and post-transcriptional regulation

Larry Reitzer

Papers

Mp02-04 invasion and assessment of intracellular bacterial colony (ibc) formation in uroepithelial cells by uropathogenic e. coli (upec) of different phylogenetic groups suggest alternate entry mechanisms

Facile transduction with P1 phage in Escherichia coli associated with urinary tract infections.

Mp02-01 comparative transcriptomics suggests convergent and divergent properties of uropathogenic escherichia coli

Nitrogen-limitation independent control of glnA (glutamine synthetase) expression in Escherichia coli by urea, several amino acids, and post-transcriptional regulation

RoleofMultiple Environmental Stimuli inControl ofTranscription froma Nitrogen-Regulated Promoter inEscherichin coli withWeakor No Activator-Binding