title: Alterations of choline phospholipid metabolism in ovarian tumor progression.
abstract: Recent characterization of abnormal phosphatidylcholine metabolism in tumor cells by nuclear magnetic resonance (NMR) has identified novel fingerprints of tumor progression that are potentially useful as clinical diagnostic indicators. In the present study, we analyzed the concentrations of phosphatidylcholine metabolites, activities of phosphocholine-producing enzymes, and uptake of [methyl-14C]choline in human epithelial ovarian carcinoma cell lines (EOC) compared with normal or immortalized ovary epithelial cells (EONT). Quantification of phosphatidylcholine metabolites contributing to the 1H NMR total choline resonance (3.20-3.24 ppm) revealed intracellular [phosphocholine] and [total choline] of 2.3 +/- 0.9 and 5.2 +/- 2.4 nmol/10(6) cells, respectively, with a glycerophosphocholine/phosphocholine ratio of 0.95 +/- 0.93 in EONT cells; average [phosphocholine] was 3- to 8-fold higher in EOC cells (P < 0.0001), becoming the predominant phosphatidylcholine metabolite, whereas average glycerophosphocholine/phosphocholine values decreased significantly to < or =0.2. Two-dimensional (phosphocholine/total choline, [total choline]) and (glycerophosphocholine/total choline, [total choline]) maps allowed separate clustering of EOC from EONT cells (P < 0.0001, 95% confidence limits). Rates of choline kinase activity in EOC cells were 12- to 24-fold higher (P < 0.03) than those in EONT cells (basal rate, 0.5 +/- 0.1 nmol/10(6) cells/h), accounting for a consistently elevated (5- to 15-fold) [methyl-14C]choline uptake after 1-hour incubation (P < 0.0001). The overall activity of phosphatidylcholine-specific phospholipase C and phospholipase D was also higher ( approximately 5-fold) in EOC cells, suggesting that both biosynthetic and catabolic pathways of the phosphatidylcholine cycle likely contribute to phosphocholine accumulation. Evidence of abnormal phosphatidylcholine metabolism might have implications in EOC biology and might provide an avenue to the development of noninvasive clinical tools for EOC diagnosis and treatment follow-up.
authors.affiliation: Section of Molecular and Cellular Imaging, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Egidio
authors.initials: E
authors.lastname: Iorio
authors.forename: Delia
authors.initials: D
authors.lastname: Mezzanzanica
authors.forename: Paola
authors.initials: P
authors.lastname: Alberti
authors.forename: Francesca
authors.initials: F
authors.lastname: Spadaro
authors.forename: Carlo
authors.initials: C
authors.lastname: Ramoni
authors.forename: Sandra
authors.initials: S
authors.lastname: D'Ascenzo
authors.forename: Danilo
authors.initials: D
authors.lastname: Millimaggi
authors.forename: Antonio
authors.initials: A
authors.lastname: Pavan
authors.forename: Vincenza
authors.initials: V
authors.lastname: Dolo
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.forename: Franca
authors.initials: F
authors.lastname: Podo
mesh_terms: D002250:Carbon Radioisotopes; D045744:Cell Line, Tumor; D002794:Choline / Q000378:metabolism / Q000493:pharmacokinetics; D002797:Choline Kinase / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010713:Phosphatidylcholines / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism; D010767:Phosphorylcholine / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D002250:Carbon Radioisotopes; D010713:Phosphatidylcholines; D010767:Phosphorylcholine; D002797:Choline Kinase; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C; D010739:Phospholipase D; D002794:Choline