Molecular Causes of the Aberrant Choline Phospholipid Metabolism in Breast Cancer

Abstract

Proton magnetic resonance spectroscopy ( 1 H MRS) consistently detects significant differences in choline phospholipid metabolites of malignant versus benign breast lesions. It is critically important to understand the molecular causes underlying these metabolic differences, because this may identify novel targets for attack in cancer cells. In this study, differences in choline membrane metabolism were characterized in breast cancer cells and normal human mammary epithelial cells (HMECs) labeled with [1,2-13 C]choline, using 1 H and 13 C magnetic resonance spectroscopy. Metabolic fluxes between membrane and water-soluble pool of choline-containing metabolites were assessed by exposing cells to [1,2-13 C]choline for long and short periods of time to distinguish between catabolic and anabolic pathways in choline metabolism. Gene expression analysis using microarrays was performed to understand the molecular mechanisms underlying these changes. Breast cancer cells exhibited increased phosphocholine (PC; P < 0.001), total choline-containing metabolites (P < 0.01), and significantly decreased glycerophosphocholine (P < 0.05) compared with normal HMECs. Decreased 13 C-enrichment was detected in choline (P < 0.001) and phosphocholine (P < 0.05, P < 0.001) of breast cancer cells compared with HMECs, indicating a higher metabolic flux from membrane phosphatidylcholine to choline and phosphocholine in breast cancer cells. Choline kinase and phospholipase C were significantly overexpressed, and lysophospholipase 1, phospholipase A2, and phospholipase D were significantly underexpressed, in breast cancer cells compared with HMECs. The magnetic resonance spectroscopy data indicated that elevated phosphocholine in breast cancer cells was primarily attributable to increased choline kinase activity and increased catabolism mediated by increased phospholipase C activity. These observations were consistent with the overexpression of choline kinase and phospholipase C detected in the microarray analyses.

The Kennedy pathway—De novo synthesis of phosphatidylethanolamine and phosphatidylcholine

“…For this reason, it has been proposed to use CK as a prognostic marker for cancer progression as well as a molecular target for the development of novel cancer chemotherapeutic agents (93-95 and references therein). Toward this goal, the use of small interfering RNA or small hairpin RNA plasmids of CK has been shown to reduce intracellular phosphocholine, selectively reduces proliferation, and increases apoptosis in breast adenocarcinoma cells, but not in normal human mammary epithelial cells (95).…”

Plasma lipidomics reveal profound perturbation of glycerophospholipids, fatty acids, and sphingolipids in diet-induced hyperlipidemia

“…PLS-DA distinguished tumor in papillary and clear cell RCC and papillary from clear cell RCC. Altered GP tissue composition occurs in cancer [107] and appears integrally associated with malignant transformation [108]. Micro-LC-QTOF/MS was used to investigate urine lipids in RCC versus healthy subjects.…”

Desorption electrospray ionization imaging mass spectrometry of lipids in rat spinal cord

“…It has been reported that alterations in the glycerophospholipid composition of tissues occur in several diseases, including cancer [9] and Alzheimer's disease [10]. Particular glycerophospholipids and their enzymatic products have been identified in malignant transformations in tissue [11,12]. In other cases, the expression of phosphatidylserine in the outer leaflet of the membrane has been found to play a role in the recognition of altered cells, such as cancer cells, by macrophages [13,14].…”