A second Warburg-like effect in cancer metabolism: The metabolic shift of glutamine-derived nitrogen

Carbon and nitrogen are essential elements for life. Glucose as a carbon source and glutamine as a nitrogen source are important nutrients for cell proliferation. About 100 years ago, it was discovered that cancer cells that have acquired unlimited proliferative capacity and undergone malignant evolution in their host manifest a cancer-specific remodeling of glucose metabolism (the Warburg effect). Only recently, however, was it shown that the metabolism of glutamine-derived nitrogen is substantially shifted from glutaminolysis to nucleotide biosynthesis during malignant progression of cancer—which might be referred to as a “second” Warburg effect. In this review, address the mechanism and relevance of this metabolic shift of glutamine-derived nitrogen in human cancer. We also examine the clinical potential of anticancer therapies that modulate the metabolic pathways of glutamine-derived nitrogen. This shift may be as important as the shift in carbon metabolism, which has long been known as the Warburg effect.     

The role of cancer metabolism in defining the success of oncolytic viro-immunotherapy

Oncolytic viruses infect, replicate in, and kill cancer cells selectively without harming normal cells. The rapidly expanding clinical development of oncolytic virotherapy is an exciting interdisciplinary field that provides insights into virology, oncology, and immunotherapy. Recent years have seen greater focus on rational design of cancer-selective viruses together with strategies to exploit their immunostimulatory capabilities, ultimately to develop powerful oncolytic cancer vaccines. However, despite great interest in the field, many important experiments are still conducted under optimum conditions in vitro, with many nutrients present in excess and with cellular stress kept to a minimum. Whilst this provides a convenient platform for cell culture, it bears little relation to the typical conditions found within a tumour in vivo, where cells are often subject to a range of metabolic and environmental stresses. Viral infection and cancer will both lead to production of metabolites that are also not present in media in vitro. Understanding how oncolytic viruses interact with cells exposed to more representative metabolic conditions in vitro represents an under-explored area of study that could provide valuable insight into the intelligent design of superior oncolytic viruses and help bridge the gap between bench and bedside. This review summarises the major metabolic pathways altered in cancer cells, during viral infection and highlights possible targets for future studies.     

Isocitrate dehydrogenase variants in cancer — Cellular consequences and therapeutic opportunities

Abnormal metabolism is common in cancer cells and often correlates with mutations in genes encoding for enzymes involved in small-molecule metabolism. Isocitrate dehydrogenase 1 (IDH1) is the most frequently mutated metabolic gene in cancer. Cancer-associated substitutions in IDH1 and IDH2 impair wild-type production of 2-oxoglutarate and reduced nicotinamide adenine dinucleotide phosphate (NADPH) from isocitrate and oxidised nicotinamide adenine dinucleotide phosphate (NADP⁺ ), and substantially promote the IDH variant catalysed conversion of 2-oxoglutarate to d-2-hydroxyglutarate (d-2HG). Elevated d-2HG is a biomarker for some cancers, and inhibition of IDH1 and IDH2 variants is being pursued as a medicinal chemistry target. We provide an overview of the types of cancer-associated IDH variants, discuss some of the proposed consequences of altered metabolism as a result of elevated d-2HG, summarise therapeutic efforts targeting IDH variants and identify areas for future research.     

Influence of training in the dark or light phase on physiologic and metabolic parameters of Wistar rats submitted to aerobic exercise

Light and dark phase training may influences rodents’ physiologic parameters because these animals have nocturnal habits. Thus, we verify the effects of the training in different photoperiods on metabolism and corporal composition of rats. Eighteen rats were divided into three groups – G1: non-trained; G2: trained in the light phase; G3: trained in the dark phase. Rats were allowed to swim for 60 min, five times per week during six weeks. Trained animals presented a smaller weight gain and fat percentage in carcass. Rats of G3 increased gastrocnemius relative weight. The adipocyte diameter of G3 rats was smaller than the other groups. The levels of the total cholesterol, low-density proteins, and triacylglycerols were decreased in animals of G2 while the glycemia was increased. Training in light phase provided more alterations in the blood biochemical profile while the training in the dark increased the gastrocnemius weight and decreased the diameter of the adipocyte.     

Differential expression of microRNAs in mouse liver under aberrant energy metabolic status

Despite years of effort, exact pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains obscure. To gain an insight into the regulatory roles of microRNAs (miRNAs) in aberrant energy metabolic status and pathogenesis of NAFLD, we analyzed the expression of miRNAs in livers of ob/ob mice, streptozotocin (STZ)-induced type 1 diabetic mice, and normal C57BL/6 mice by miRNA microarray. Compared with normal C57BL/6 mice, ob/ob mice showed upregulation of eight miRNAs and downregulation of four miRNAs in fatty livers. Upregulation of miR-34a and downregulation of miR-122 was found in livers of STZ-induced diabetic mice. These results demonstrate that distinct miRNAs are strongly dysregulated in NAFLD and hyperglycemia. Comparison between miRNA expressions in livers of ob/ob mice and STZ-administered mice further revealed upregulation of four miRNAs and downregulation of two miRNAs in livers of ob/ob mice, indicating that these miRNAs may represent a molecular signature of NAFLD. A distinctive miRNA expression pattern was identified in ob/ob mouse liver, and hierarchical clustering of this pattern could clearly discriminate ob/ob mice from either normal C57BL/6 mice or STZ-administered mice. These findings suggest an important role of miRNAs in hepatic energy metabolism and implicate the participation of miRNAs in the pathophysiological processes of NAFLD.     

Impact on energy metabolism of quantitative and functional cyclosporine-induced damage of kidney mitochondria

In this study we have measured, under experimental conditions which maintained efficient coupling, respiratory intensity, respiratory control, oxidative phosphorylation capacity and protonmotive force. Succinate cytochrome-c reductase and cytochrome-c oxidase activities were also studied. These investigations were carried out using kidney mitochondria from cyclosporine-treated rats (in vivo studies) and from untreated rats in the presence of cyclosporine (in vitro studies). Inhibition of respiratory intensity by cyclosporine did not exceed 21.1% in vitro and 15.9% in vivo. Since there was no in vitro inhibition of succinate cytochrome-c reductase and cytochrome-c oxidase activities, the slowing of electron flow observed can be interpreted as a consequence of an effect produced by cyclosporine between cytochromes b and c₁. Cyclosporine had no effect on respiratory control either in vitro or in vivo. Statistically significant inhibition of the oxidative phosphorylation was observed both in vitro (6.6%) and in vivo (12.1%). Moreover, cyclosporine did not induce any change of membrane potential either in vivo or in vitro. Our findings show that cyclosporine is neither a protonophore, nor a potassium ionophore. In cyclosporine-treated rats we noticed a decrease of protein in subcellular fraction, including the mitochondrial fraction. The role of the inhibition respiratory characteristics by cyclosporine in nephrotoxicity in vivo must take account of these two parameters: inhibition of the respiratory characteristics measured in vitro and diminution of mitochondrial protein in cyclosporine-treated rats.     

Reduction of 4-androstene-3,17-dione by growing cucumber plants

4-[4-¹⁴C]Androstene-3,17-dione was applied to the leaves of growing cucumber plants, Cucumis sativus, twice a week. Four weeks after the first     

Prolactin,hypercalcemia and corpuscles of stannius in seawater eels

In intact eels in sea water (SW), ovine prolactin (PRL) treatment induces hypercalcemia, but its mechanism of action, which is discussed, remains to be defined. Corpuscles of Stannius (CSt) are modified simultaneously: two cell categories then become evident. The first cell type (type 1) predominates; it has an oval shape and large granules, it shows a nuclear and nucleolar hypertrophy and a mitotic activity, and appears greatly stimulated by PRL; it may elaborate a hypocalcemic factor (hypocalcin) which would compensate for the PRL-induced hypercalcemia. A similar effect, although slightly less intense, is detected in hypophysectomized-PRL treated eels in SW. A second cell type (type 2), is more elongated, smaller in size, and has an oval nucleus and fine granules. Scarcely less active in SW, it is significantly stimulated by PRL despite an increased blood sodium and potassium level. This experiment does not help to clarify its function.