Une connaissance de la strategie biochimique des cellules cancereuses et de la «voie royale» pour la conception de la chimiotherapie anticancereuse dirigee par l'enzymogramme. Dans cet article on souligne l'essence et la substance des progres theoriques et experimentaux vers une connaissance de la strategie biochimique et de la logique de l'expression des genes dans les cellules cancereuses et on identifie un programme enzymatique et metabolique commun dans les diverses tumeurs animales et humaines

https://cancerres.aacrjournals.org/content/canres/43/8/3466.full.pdf

Biochemical Strategy of Cancer Cells and the Design of Chemotherapy: G. H. A. Clowes Memorial Lecture

Glutamine is the most abundant circulating amino acid in blood and muscle and is critical for many fundamental cell functions in cancer cells, including synthesis of metabolites that maintain mitochondrial metabolism; generation of antioxidants to remove reactive oxygen species; synthesis of nonessential amino acids (NEAAs), purines, pyrimidines, and fatty acids for cellular replication; and activation of cell signaling. In light of the pleiotropic role of glutamine in cancer cells, a comprehensive understanding of glutamine metabolism is essential for the development of metabolic therapeutic strategies for targeting cancer cells. In this article, we review oncogene-, tumor suppressor–, and tumor microenvironment–mediated regulation of glutamine metabolism in cancer cells. We describe the mechanism of glutamine's regulation of tumor proliferation, metastasis, and global methylation. Furthermore, we highlight the therapeutic potential of glutamine metabolism and emphasize that clinical application of in vi...

Glutaminolysis: A Hallmark of Cancer Metabolism

Enzymes of the pyrimidine base catabolism, dihydrouracil dehydrogenase (EC 1.3.1.2), dihydropyrimidinase (EC 3.5.2.2), and β-ureidopropionase (EC 3.5.1.6) were compared in the cytosolic extract of several normal and neoplastic human tissues. The activity was measured by following the catabolism of [6-14C]-uracil to dihydrouracil, carbamyl-β-alanine, and β-alanine. Substrate inhibition, hysteresis, allosterism, and the lack of dihydropyrimidinase are pointed out as special problems in assaying enzymes of pyrimidine degradation. The activity of dihydrouracil dehydrogenase has been demonstrated in several human extrahepatic tissues and tumors. The enzyme is rate limiting in extrahepatic solid tumors but not in their normal counterparts. Some of these solid tumors contain greater amounts of activity than do their normal equivalents, which encourages the use of inhibitors of this enzyme in conjunction with treatment of these tumors by 5-fluorouracil. Because of the lack of a pattern in dihydrouracil dehydrogenase activity between tumors and normal tissues, the enzyme is not a good marker for tumorigenicity. Dihydropyrimidinase, on the other hand, is highly active in all solid tumors studied but not in their normal counterparts; therefore, we suggest that dihydropyrimidinase can serve as a good marker of tumorigenicity as well as a target for cancer chemotherapy of human solid tumors.

https://cancerres.aacrjournals.org/content/canres/45/11_Part_1/5405.full.pdf

Enzymes of Uracil Catabolism in Normal and Neoplastic Human Tissues

Microsporidia comprise a large phylum of obligate intracellular eukaryotes that are fungal-related parasites responsible for widespread disease, and here we address questions about microsporidia biology and evolution. We sequenced three microsporidian genomes from two species, Nematocida parisii and Nematocida sp1, which are natural pathogens of Caenorhabditis nematodes and provide model systems for studying microsporidian pathogenesis. We performed deep sequencing of transcripts from a time course of N. parisii infection. Examination of pathogen gene expression revealed compact transcripts and a dramatic takeover of host cells by Nematocida. We also performed phylogenomic analyses of Nematocida and other microsporidian genomes to refine microsporidian phylogeny and identify evolutionary events of gene loss, acquisition, and modification. In particular, we found that all microsporidia lost the tumor-suppressor gene retinoblastoma, which we speculate could accelerate the parasite cell cycle and increase the mutation rate. We also found that microsporidia acquired transporters that could import nucleosides to fuel rapid growth. In addition, microsporidian hexokinases gained secretion signal sequences, and in a functional assay these were sufficient to export proteins out of the cell; thus hexokinase may be targeted into the host cell to reprogram it toward biosynthesis. Similar molecular changes appear during formation of cancer cells and may be evolutionary strategies adopted independently by microsporidia to proliferate rapidly within host cells. Finally, analysis of genome polymorphisms revealed evidence for a sexual cycle that may provide genetic diversity to alleviate problems caused by clonal growth. Together these events may explain the emergence and success of these diverse intracellular parasites.

/pdf/microsporidian-genome-analysis-reveals-evolutionary-1usp6g5gk9.pdf

Microsporidian genome analysis reveals evolutionary strategies for obligate intracellular growth.

While specific genes are hypermethylated in the genome of cancer cells, overall methylcytosine content is often decreased as a consequence of hypomethylation affecting many repetitive sequences. Hy...

Causes and consequences of DNA hypomethylation in human cancer.

AN insight into the biochemical strategy of cancer cells has been achieved by the conceptual and experimental approach provided by the molecular correlation concept1,2. Studies carried out using this approach with model systems of rat hepatomas and kidney tumours of different growth rates revealed a biochemical imbalance in cancer cells, which manifested itself in progressive changes in activities of key enzymes and overall metabolic pathways that correlated with tumour growth rate1,2. Some of these biochemical alterations have been shown to apply to human primary liver3 and kidney4 carcinomas. Those alterations in gene expression that are linked to the increase in the expression of malignancy are manifested in the increased activities of key glycolytic-, purine-, pyrimidine-, DNA- and polyamine-synthesising enzymes1–8. Concurrently, decreases occur in the activities of the key enzymes of gluconeogenesis, purine and pyrimidine catabolism and of the urea cycle1–5,9,10. In addition to such a progression-linked (growth-rate-linked) metabolic imbalance, the reprogramming of gene expression in cancer cells entails transformation-linked alterations that are present in all hepatomas irrespective of growth rate or extent of differentiation1,2,11–15.Here we report that CTP synthetase (UTP:L-glutamine amido ligase, EC 6.3.4.2) increased in all the hepatomas examined, the activity being highest in the rapidly growing tumours. Thus, in liver neoplasia the activity of this enzyme is both transformation- and progression-linked. CTP synthetase activity was also markedly increased in transplantable kidney tumours in the rat and in primary renal cell carcinomas in man.

Harutoshi Kizaki

Papers

Increased CTP synthetase activity in cancer cells.

Biochemical strategy of the genome as expressed in regulation of pyrimidine metabolism

Biochemical commitment to replication in cancer cells.

Biochemical pharmacology of acivicin in rat hepatoma cells

Colon tumor: Enzymology of the neoplastic program