Human Phospholipase D Activity Transiently Regulates Pyrimidine Biosynthesis in Malignant Gliomas

Thomas P. Mathews, Salisha Hill, Kristie L. Rose, Pavlina T. Ivanova, Craig W. Lindsley, H. Alex Brown

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1258-1268
Number of pages11
JournalACS chemical biology
Volume10
Issue number5
DOIs
StatePublished - May 15 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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