One-carbon metabolism in cancer

Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism

Social Work Assessment: Case Theory Construction

To intervene effectively, social workers need to make sense of clients and their situations. A case theory approach to assessment pro-vides a framework to formulate assessments that are clear and directly related to the real-world problems clients present Explaining the problem situation, case theory forms the foundation for selection of intervention strategies and methods to achieve change. Build-ing case theory requires practitioner abilities to form concepts, relate concepts into propositions, develop hypotheses, and organize these into a coherent whole. Including case background information, observations and relevant professional literature, case theory pre-sents an accurate and cogent comprehension of the client Two case examples of depression illustrate the important relationship among concepts, empirical referents, propositions, general theorles, and intervention, highlighting how case theory guides practice. AN OVERARCHING INQUIRY DIRECTS this article: How do social workers figure out what is going on with clients? Embedded within is another question: What is the point of this knowledge? I offer here a case theory framework for use by social workers to make sense of cli-ents and their situations and connect that comprehension to treatment planning and intervention

Discovery of extreme particle acceleration in the microquasar Cygnus X-3

The study of relativistic particle acceleration is a major topic of high-energy astrophysics. It is well known that massive black holes in active galaxies can release a substantial fraction of their accretion power into energetic particles, producing gamma-rays and relativistic jets. Galactic microquasars (hosting a compact star of 1-10 solar masses which accretes matter from a binary companion) also produce relativistic jets. However, no direct evidence of particle acceleration above GeV energies has ever been obtained in microquasar ejections, leaving open the issue of the occurrence and timing of extreme matter energization during jet formation. Here we report the detection of transient gamma-ray emission above 100 MeV from the microquasar Cygnus X-3, an exceptional X-ray binary which sporadically produces powerful radio jets. Four gamma-ray flares (each lasting 1-2 days) were detected by the AGILE satellite simultaneously with special spectral states of Cygnus X-3 during the period mid-2007/mid-2009. Our observations show that very efficient particle acceleration and gamma-ray propagation out of the inner disk of a microquasar usually occur a few days before major relativistic jet ejections. Flaring particle energies can be thousands of times larger than previously detected maximum values (with Lorentz factors of 105 and 102 for electrons and protons, respectively). We show that the transitional nature of gamma-ray flares and particle acceleration above GeV energies in Cygnus X-3 is clearly linked to special radio/X-ray states preceding strong radio flares. Thus gamma-rays provide unique insight into the nature of physical processes in microquasars.Comment: 29 pages (including Supplementary Information), 8 figures, 2 tables version submitted to Nature on August 7, 2009 (accepted version available at http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature08578.pdf

Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis

Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood [1, 2]. Using a metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.National Institutes of Health (U.S.)National Cancer Institute (U.S.)Smith Family FoundationDamon Runyon Cancer Research FoundationBurroughs Wellcome Fun

L-2-hydroxyglutarate production arises from non-canonical enzyme function at acidic pH

The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D(R)- or L(S)- enantiomer, each of which inhibits alpha-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via ‘promiscuous’ reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function