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Lane A.N.,Center for Regulatory and Environmental Analytical Metabolomics | Lane A.N.,University of Louisville | Gouw A.,Graduate Program in Pathobiology | Tsukamoto T.,Johns Hopkins University | And 11 more authors.
Cell Metabolism | Year: 2012

Because MYC plays a causal role in many human cancers, including those with hypoxic and nutrient-poor tumor microenvironments, we have determined the metabolic responses of a MYC-inducible human Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, using stable isotope-resolved metabolomics. Using [U- 13C]-glucose as the tracer, both glucose consumption and lactate production were increased by MYC expression and hypoxia. Using [U- 13C, 15N]-glutamine as the tracer, glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased. Their 13C-labeling patterns demonstrate an alternative energy-generating glutaminolysis pathway involving a glucose-independent TCA cycle. The essential role of glutamine metabolism in cell survival and proliferation under hypoxia and glucose deficiency makes them susceptible to the glutaminase inhibitor BPTES and hence could be targeted for cancer therapy. © 2012 Elsevier Inc.

Higashi R.M.,Center for Regulatory and Environmental Analytical Metabolomics | Higashi R.M.,University of Louisville
Analytical Chemistry | Year: 2012

We describe a preconcentration device that may be suitable for quantitative analysis of trace volatile ketones and aldehydes in ambient air as well as in human breath. The approach is based on microreactor chips fabricated from silicon wafers. The microreactors have thousands of micropillars in microfluidic channels for uniformly distributing a gaseous sample flowing through the chips. The surfaces of the micropillars are functionalized with a quaternary ammonium aminooxy salt, [2-(aminooxy)ethyl]-N,N,N-trimethylammonium iodide (ATM), for trapping trace ketones and aldehydes by means of oximation reactions. ATM adducts and unreacted ATM are eluted from the microreactor with less than 40 μL of methanol and directly analyzed by nanospray Fourier transform ion cyclotron resonance (FTICR) mass spectrometry (MS). Ketones and aldehydes at levels of 1 ppbv have been detected using this microreactor and FTICR-MS system. © 2011 American Chemical Society.

Ren J.-G.,Beth Israel Deaconess Medical Center | Seth P.,Beth Israel Deaconess Medical Center | Clish C.B.,The Broad Institute of MIT and Harvard | Lorkiewicz P.K.,Center for Regulatory and Environmental Analytical Metabolomics | And 8 more authors.
Scientific Reports | Year: 2014

Mitochondrial malic enzyme 2 (ME2) catalyzes the oxidative decarboxylation of malate to yield CO 2 and pyruvate, with concomitant reduction of dinucleotide cofactor NAD + or NADP +. We find that ME2 is highly expressed in many solid tumors. In the A549 non-small cell lung cancer (NSCLC) cell line, ME2 depletion inhibits cell proliferation and induces cell death and differentiation, accompanied by increased reactive oxygen species (ROS) and NADP + /NADPH ratio, a drop in ATP, and increased sensitivity to cisplatin. ME2 knockdown impacts phosphoinositide-dependent protein kinase 1 (PDK1) and phosphatase and tensin homolog (PTEN) expression, leading to AKT inhibition. Depletion of ME2 leads to malate accumulation and pyruvate decrease, and exogenous cell permeable dimethyl-malate (DMM) mimics the ME2 knockdown phenotype. Both ME2 knockdown and DMM treatment reduce A549 cell growth in vivo. Collectively, our data suggest that ME2 is a potential target for cancer therapy. © 2014 Macmillan Publishers Limited. All rights reserved.

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