title: Human phospholipase D activity transiently regulates pyrimidine biosynthesis in malignant gliomas.
abstract: Cancer cells reorganize their metabolic pathways to fuel demanding rates of proliferation. Oftentimes, these metabolic phenotypes lie downstream of prominent oncogenes. The lipid signaling molecule phosphatidic acid (PtdOH), which is produced by the hydrolytic enzyme phospholipase D (PLD), has been identified as a critical regulatory molecule for oncogenic signaling in many cancers. In an effort to identify novel regulatory mechanisms for PtdOH, we screened various cancer cell lines, assessing whether treatment of cancer models with PLD inhibitors altered production of intracellular metabolites. Preliminary findings lead us to focus on how deoxyribonucleoside triphosphates (dNTPs) are altered upon PLD inhibitor treatment in gliomas. Using a combination of proteomics and small molecule intracellular metabolomics, we show herein that PtdOH acutely regulates the production of these pyrimidine metabolites through activation of CAD via mTOR signaling pathways independently of Akt. These changes are responsible for decreases in dNTP production after PLD inhibitor treatment. Our data identify a novel regulatory role for PLD activity in specific cancer types.
authors: †Department of Pharmacology and The Vanderbilt Ingram Cancer Center, ‡The Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, §Department of Chemistry, ∥The Vanderbilt Institute of Chemical Biology, ⊥The Vanderbilt Mass Spectrometry Research Center, and #Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
authors: Thomas P
authors: TP
authors: Mathews
authors: †Department of Pharmacology and The Vanderbilt Ingram Cancer Center, ‡The Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, §Department of Chemistry, ∥The Vanderbilt Institute of Chemical Biology, ⊥The Vanderbilt Mass Spectrometry Research Center, and #Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
authors: Salisha
authors: S
authors: Hill
authors: †Department of Pharmacology and The Vanderbilt Ingram Cancer Center, ‡The Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, §Department of Chemistry, ∥The Vanderbilt Institute of Chemical Biology, ⊥The Vanderbilt Mass Spectrometry Research Center, and #Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
authors: Kristie L
authors: KL
authors: Rose
authors: †Department of Pharmacology and The Vanderbilt Ingram Cancer Center, ‡The Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, §Department of Chemistry, ∥The Vanderbilt Institute of Chemical Biology, ⊥The Vanderbilt Mass Spectrometry Research Center, and #Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
authors: Pavlina T
authors: PT
authors: Ivanova
authors: †Department of Pharmacology and The Vanderbilt Ingram Cancer Center, ‡The Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, §Department of Chemistry, ∥The Vanderbilt Institute of Chemical Biology, ⊥The Vanderbilt Mass Spectrometry Research Center, and #Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
authors: Craig W
authors: CW
authors: Lindsley
authors: †Department of Pharmacology and The Vanderbilt Ingram Cancer Center, ‡The Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, §Department of Chemistry, ∥The Vanderbilt Institute of Chemical Biology, ⊥The Vanderbilt Mass Spectrometry Research Center, and #Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
authors: H Alex
authors: HA
authors: Brown
mesh_terms: D000595:Amino Acid Sequence; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005910:Glioma / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011743:Pyrimidines / Q000096:biosynthesis*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D010739:Phospholipase D
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