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ACS Chem Biol. 2015 May 15;10(5):1258-68. doi: 10.1021/cb500772c. Epub 2015 Feb 17.

Human phospholipase D activity transiently regulates pyrimidine biosynthesis in malignant gliomas.

Author information

1
†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.

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.

PMID:
25646564
PMCID:
PMC4433586
DOI:
10.1021/cb500772c
[Indexed for MEDLINE]
Free PMC Article

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