title: Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis.
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.
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors (IfADO),  University of Dortmund, 44139 Dortmund,  Germany.
authors.forename: Joanna D
authors.initials: JD
authors.lastname: Stewart
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Marchan
authors.forename: Michaela S
authors.initials: MS
authors.lastname: Lesjak
authors.forename: Joerg
authors.initials: J
authors.lastname: Lambert
authors.forename: Roland
authors.initials: R
authors.lastname: Hergenroeder
authors.forename: James K
authors.initials: JK
authors.lastname: Ellis
authors.forename: Chung-Ho
authors.initials: CH
authors.lastname: Lau
authors.forename: Hector C
authors.initials: HC
authors.lastname: Keun
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
authors.forename: Juergen
authors.initials: J
authors.lastname: Schiller
authors.forename: Mandy
authors.initials: M
authors.lastname: Eibisch
authors.forename: Christian
authors.initials: C
authors.lastname: Hedberg
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.forename: Berno
authors.initials: B
authors.lastname: Tanner
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.forename: Jens
authors.initials: J
authors.lastname: Sagemueller
authors.forename: Hagen
authors.initials: H
authors.lastname: Staude
authors.forename: Eric
authors.initials: E
authors.lastname: Steiner
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002794:Choline / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000201:enzymology* / Q000556:secondary; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000556:secondary; D010740:Phospholipases / Q000235:genetics / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051571:Protein Kinase C-alpha; C573929:EDI3 protein, mouse; C573928:GPCPD1 protein, human; D010740:Phospholipases; D010727:Phosphoric Diester Hydrolases; C038133:glycerophosphodiester phosphodiesterase; D002794:Choline