期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 21, 页码 8155-8160出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1117654109
关键词
glycerophosphodiesterase 5; phosphatidic acid; lysophosphatidic acid; glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae); glycerophosphodiester phosphodiesterase domain containing 6
资金
- Imperial College London
- European Union [223188]
- LipidomicNET [202272]
- DETECTIVE [266838]
- BMBF (German Federal Ministry of Education and Research)
- EPSRC (Engineering and Physical Sciences Research Council) Centre for Doctoral Training Studentship from the Institute of Chemical Biology (Imperial College, London)
- Medical Research Council [G0801056B] Funding Source: researchfish
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, wehave 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 PKC alpha 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.
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