Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis
- 8 May 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (21), 8155-8160
- https://doi.org/10.1073/pnas.1117654109
Abstract
Metastasis from primary tumors remains a major problem for tumor therapy. In the search for markers of metastasis and more effective therapies, the tumor metabolome is relevant because of its importance to the malignant phenotype and metastatic capacity of tumor cells. Altered choline metabolism is a hallmark of cancer. More specifically, a decreased glycerophosphocholine (GPC) to phosphocholine (PC) ratio was reported in breast, ovarian, and prostate cancers. Improved strategies to exploit this altered choline metabolism are therefore required. However, the critical enzyme cleaving GPC to produce choline, the initial step in the pathway controlling the GPC/PC ratio, remained unknown. In the present work, we have identified the enzyme, here named EDI3 (endometrial differential 3). Purified recombinant EDI3 protein cleaves GPC to form glycerol-3-phosphate and choline. Silencing EDI3 in MCF-7 cells decreased this enzymatic activity, increased the intracellular GPC/PC ratio, and decreased downstream lipid metabolites. Downregulating EDI3 activity inhibited cell migration via disruption of the PKCα signaling pathway, with stable overexpression of EDI3 showing the opposite effect. EDI3 was originally identified in our screening study comparing mRNA levels in metastasizing and nonmetastasizing endometrial carcinomas. Both Kaplan–Meier and multivariate analyses revealed a negative association between high EDI3 expression and relapse-free survival time in both endometrial (P < 0.001) and ovarian (P = 0.029) cancers. Overall, we have identified EDI3, a key enzyme controlling GPC and choline metabolism. Because inhibition of EDI3 activity corrects the GPC/PC ratio and decreases the migration capacity of tumor cells, it represents a possible target for therapeutic intervention.This publication has 45 references indexed in Scilit:
- Hallmarks of Cancer: The Next GenerationCell, 2011
- A Novel Glycerophosphodiester Phosphodiesterase, GDE5, Controls Skeletal Muscle Development via a Non-enzymatic Mechanism*Online Journal of Public Health Informatics, 2010
- Induction of fatty acid synthesis is a key requirement for phagocytic differentiation of human monocytesProceedings of the National Academy of Sciences of the United States of America, 2010
- Magnetic Resonance Spectroscopy in Metabolic and Molecular Imaging and Diagnosis of CancerChemical Reviews, 2010
- Activation of Phosphatidylcholine Cycle Enzymes in Human Epithelial Ovarian Cancer CellsCancer Research, 2010
- Phosphatidic acid signaling to mTOR: Signals for the survival of human cancer cellsBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2009
- Mass spectrometric analysis of lipid species of human circulating blood cellsBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2008
- GDPD5 is a glycerophosphocholine phosphodiesterase that osmotically regulates the osmoprotective organic osmolyte GPCProceedings of the National Academy of Sciences of the United States of America, 2008
- The emerging role of lysophosphatidic acid in cancerNature Reviews Cancer, 2003
- Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancersBiochemical and Biophysical Research Communications, 2002