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      Metabolomic Profiling Reveals Biochemical Pathways and Biomarkers Associated with Pathogenesis in Cystic Fibrosis Cells*

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          Abstract

          Cystic fibrosis (CF) is a life-shortening disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. To gain an understanding of the epithelial dysfunction associated with CF mutations and discover biomarkers for therapeutics development, untargeted metabolomic analysis was performed on primary human airway epithelial cell cultures from three separate cohorts of CF patients and non-CF subjects. Statistical analysis revealed a set of reproducible and significant metabolic differences between the CF and non-CF cells. Aside from changes that were consistent with known CF effects, such as diminished cellular regulation against oxidative stress and osmotic stress, new observations on the cellular metabolism in the disease were generated. In the CF cells, the levels of various purine nucleotides, which may function to regulate cellular responses via purinergic signaling, were significantly decreased. Furthermore, CF cells exhibited reduced glucose metabolism in glycolysis, pentose phosphate pathway, and sorbitol pathway, which may further exacerbate oxidative stress and limit the epithelial cell response to environmental pressure. Taken together, these findings reveal novel metabolic abnormalities associated with the CF pathological process and identify a panel of potential biomarkers for therapeutic development using this model system.

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          Most cited references 40

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          Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.

          Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.
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            Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.

            Overlapping complementary DNA clones were isolated from epithelial cell libraries with a genomic DNA segment containing a portion of the putative cystic fibrosis (CF) locus, which is on chromosome 7. Transcripts, approximately 6500 nucleotides in size, were detectable in the tissues affected in patients with CF. The predicted protein consists of two similar motifs, each with (i) a domain having properties consistent with membrane association and (ii) a domain believed to be involved in ATP (adenosine triphosphate) binding. A deletion of three base pairs that results in the omission of a phenylalanine residue at the center of the first predicted nucleotide-binding domain was detected in CF patients.
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              Organic osmolytes as compatible, metabolic and counteracting cytoprotectants in high osmolarity and other stresses.

               Paul Yancey (2005)
              Organic osmolytes are small solutes used by cells of numerous water-stressed organisms and tissues to maintain cell volume. Similar compounds are accumulated by some organisms in anhydrobiotic, thermal and possibly pressure stresses. These solutes are amino acids and derivatives, polyols and sugars, methylamines, methylsulfonium compounds and urea. Except for urea, they are often called ;compatible solutes', a term indicating lack of perturbing effects on cellular macromolecules and implying interchangeability. However, these features may not always exist, for three reasons. First, some of these solutes may have unique protective metabolic roles, such as acting as antioxidants (e.g. polyols, taurine, hypotaurine), providing redox balance (e.g. glycerol) and detoxifying sulfide (hypotaurine in animals at hydrothermal vents and seeps). Second, some of these solutes stabilize macromolecules and counteract perturbants in non-interchangeable ways. Methylamines [e.g. trimethylamine N-oxide (TMAO)] can enhance protein folding and ligand binding and counteract perturbations by urea (e.g. in elasmobranchs and mammalian kidney), inorganic ions, and hydrostatic pressure in deep-sea animals. Trehalose and proline in overwintering insects stabilize membranes at subzero temperatures. Trehalose in insects and yeast, and anionic polyols in microorganisms around hydrothermal vents, can protect proteins from denaturation by high temperatures. Third, stabilizing solutes appear to be used in nature only to counteract perturbants of macromolecules, perhaps because stabilization is detrimental in the absence of perturbation. Some of these solutes have applications in biotechnology, agriculture and medicine, including in vitro rescue of the misfolded protein of cystic fibrosis. However, caution is warranted if high levels cause overstabilization of proteins.
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                Author and article information

                Journal
                J Biol Chem
                jbc
                jbc
                JBC
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology (9650 Rockville Pike, Bethesda, MD 20814, U.S.A. )
                0021-9258
                1083-351X
                1 October 2010
                30 July 2010
                30 July 2010
                : 285
                : 40
                : 30516-30522
                Affiliations
                From []Cystic Fibrosis Foundation Therapeutics, Inc., Bethesda, Maryland 20814,
                the [§ ]Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15251, and
                []Metabolon, Inc., Durham, North Carolina 27713
                Author notes
                [1 ] To whom correspondence should be addressed: Metabolon, Inc., 800 Capitola Dr., Suite 1, Durham, NC 27713. Tel.: 919-287-3356; Fax: 919-572-1721; E-mail: lguo@ 123456metabolon.com .
                Article
                M110.140806
                10.1074/jbc.M110.140806
                2945545
                20675369
                © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

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                Categories
                Metabolism
                Molecular Bases of Disease

                Biochemistry

                energy metabolism, purine, cystic fibrosis, metabolomics, oxidative stress

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