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 phosphocholineproducing enzymes, and uptake of [methyl-14 C]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 1 H NMR total choline resonance (3.20-3.24 ppm) revealed intracellular [phosphocholine] and [total choline] of 2.3 F 0.9 and 5.2 F 2.4 nmol/10 6 cells, respectively, with a glycerophosphocholine/phosphocholine ratio of 0.95 F 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 V0.2. 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 F 0.1 nmol/10 6 cells/h), accounting for a consistently elevated (5-to 15-fold) [methyl-14 C]-choline uptake after 1-hour incubation (P < 0.0001). The overall activity of phosphatidylcholine-specific phospholipase C and phospholipase D was also higher (f5-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. (Cancer Res 2005; 65(20): 9369-76)

Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis

“…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. I t is widely accepted that choline metabolism represents a critical aspect of the tumor metabolome (1)(2)(3)(4). As cells undergo malignant transformation, there is an overall increase in total choline metabolites and phosphocholine (PC).…”

In vivo magnetic resonance spectroscopy for ovarian cancer diagnostics: quantification by the fast Padé transform

“…Since the histopathology of the present case was borderline, a relatively small PC peak could be expected. Given that PC is a recognized biomarker of malignant transformation [64,65], with Padé optimization it now becomes possible to assess this key metabolite non-invasively, with an anticipated improvement in identifying ovarian cancer. Quantification of PC could also aid in timelier detection of ovarian cancer progression, based upon studies of ovarian tumor cell lines [64].…”

“…Via proton MRS, only mean intracellular Lac at 1.32 ppm was found to be significantly higher in cells obtained from ovarian cancers as compared to benign ovarian cysts; the total Cho level was marginally significantly higher in the cancer cells [63]. The chemical shift region between 3.20 and 3.24 ppm has been examined in more detail, comparing human epithelial ovarian carcinoma cell lines with normal or immortalized ovarian epithelial cells, with phosphocholine (PC) found to be three-to eight-fold higher in the cancer cells [64]. It has thus been suggested that there may be possibilities for improving the diagnostic yield of MRS for ovarian cancer by identifying the components of total Cho, in particular PC, which is a recognized biomarker of malignant transformation [65].…”

Changes in choline metabolism as potential biomarkers of phospholipase Cγ1 inhibition in human prostate cancer cells

“…In breast, ovarian, and prostate carcinoma cells, stepwise increases in cellular phosphocholine content and the phosphocholine/glycerophosphocholine ratio were observed in cell lines with increasing malignant potential (30,49,50). An increase in total choline-containing compounds and the phosphocholine/glycerophosphocholine ratio was also reported in a highly metastatic murine breast tumor model relative to its less metastatic counterpart (51).…”

“…They are believed to be a consequence of increased rates of choline transport and phosphorylation and/or changes in levels of phospholipid metabolizing enzymes occurring in cancer relative to normal cells (30)(31)(32)(33).…”