Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo.

Diverse tumor metabolic phenotypes are influenced by the environment and genetic lesions. Whether these phenotypes extend to rhabdomyosarcoma (RMS) and how they might be leveraged to design new therapeutic approaches remains an open question. Thus, we utilized a Pax7; Nras; p53 (P7NP) murine model of sarcoma with mutations that most frequently occur in human embryonal RMS.

Nucleotide metabolism is linked to cysteine availability.

The small molecule erastin inhibits the cystine-glutamate antiporter, system x, which leads to intracellular cysteine and glutathione depletion. This can cause ferroptosis, which is an oxidative cell death process characterized by uncontrolled lipid peroxidation. Erastin and other ferroptosis inducers have been shown to affect metabolism but the metabolic effects of these drugs have not been systematically studied.

Sestrin mediates detection of and adaptation to low-leucine diets in Drosophila.

Mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple nutrients, including the essential amino acid leucine. Recent work in cultured mammalian cells established the Sestrins as leucine-binding proteins that inhibit mTORC1 signalling during leucine deprivation, but their role in the organismal response to dietary leucine remains elusive. Here we find that Sestrin-null flies (Sesn) fail to inhibit mTORC1 or activate autophagy after acute leucine starvation and have impaired development and a shortened lifespan on a low-leucine diet.

Metabolomics: insights into plant-based diets.

Plant-based diets exclude or substantially limit the consumption of meat and animal products and are of growing interest to many due to their sustainability and health benefits (Eshel et al, 2016). Veganism is an extreme type of plant-based diet which excludes the consumption of all animal-derived foods such as meat, eggs, and dairy, as well as foods containing animal-derived ingredients. In adults, for example, certain observational studies have suggested lower body mass index, total cholesterol, LDL-cholesterol, decreased incidence and mortality from ischemic heart disease, and decreased incidence of cancer in vegans and vegetarians versus omnivores (Dinu et al, 2017).

The Molecular Link from Diet to Cancer Cell Metabolism.

Malignant cells remodel their metabolism to meet the demands of uncontrolled cell proliferation. These demands lead to differential requirements in energy, biosynthetic precursors, and signaling intermediates. Both genetic programs arising from oncogenic events and transcriptional programs and epigenomic events are important in providing the necessary metabolic network activity.

Evolved resistance to partial GAPDH inhibition results in loss of the Warburg effect and in a different state of glycolysis.

Aerobic glycolysis or the Warburg effect (WE) is characterized by increased glucose uptake and incomplete oxidation to lactate. Although the WE is ubiquitous, its biological role remains controversial, and whether glucose metabolism is functionally different during fully oxidative glycolysis or during the WE is unknown. To investigate this question, here we evolved resistance to koningic acid (KA), a natural product that specifically inhibits glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-controlling glycolytic enzyme, during the WE.

Serine synthesis through PHGDH coordinates nucleotide levels by maintaining central carbon metabolism.

Phosphoglycerate dehydrogenase (PHGDH) catalyzes the committed step in de novo serine biosynthesis. Paradoxically, PHGDH and serine synthesis are required in the presence of abundant environmental serine even when serine uptake exceeds the requirements for nucleotide synthesis. Here, we establish a mechanism for how PHGDH maintains nucleotide metabolism.

Glucose Metabolism in Cancer: The Saga of Pyruvate Kinase Continues.

Altered glucose metabolism is common in cancer. In this issue of Cancer Cell, Morita et al. report new mouse models that express specific isoforms of pyruvate kinase to study glycolysis in tumors.