Differential routing of choline in implanted breast cancer and normal organs

Abstract

Choline is an essential nutrient participating as the initial substrate in major metabolic pathways. The differential metabolic routing of choline was investigated in MCF7 human breast cancer implanted in nude mice and in the kidney, liver, and brain of these mice. The distribution of metabolites following infusion of [1,2-13 C]-choline was monitored by 13 Choline, a quaternary amine, is an essential nutrient for humans (1,2) and plays a critical role in brain development (3). The metabolism of choline is partitioned among three major pathways: 1) phosphorylation leading to the CDP-choline pathway (known also as the Kennedy pathway) for the synthesis of phosphatidylcholine (PtdCho); 2) acetylation to synthesize the neurotransmitter acetylcholine; 3) oxidation to produce the methyl donor betaine and S-adenosylmethionine (Fig. 1). Following uptake of choline, it is first converted to phosphocholine (PCho) via the CDP-choline pathway, or to betaine through the oxidation pathway, or to acetylcholine, all water-soluble metabolites that can be present in appreciable amounts (mM range). Thus, the amount of these metabolites can be determined by choline transport and/or by the activities of the enzymes involved in their synthesis and further metabolism. Glycerophosphocholine (GPCho) is also a water-soluble, choline-derived metabolite; however, unlike the other metabolites described above, which are synthesized from choline in one or two steps, it is a breakdown product of PtdCho and therefore the regulation of its content is complex. The distribution of the water-soluble choline metabolites among the various pathways varies with tissue type and can be modulated by changing the choline intake via diet or direct infusion.High levels of choline metabolites including PCho and GPCho were previously observed by 31 P and 1 H magnetic resonance spectroscopy (MRS) in various malignancies and specifically in breast cancer (4 -11). The magnitude of the 1 H MRS signal of the trimethylamine moiety shared by choline and its derivatives was previously shown to aid in the diagnosis of breast cancer (5-7); however, it was not possible to resolve this signal. Previous studies monitored in vivo the uptake and metabolism of choline in mammary carcinoma using 31 P MRS to follow phosphonium-choline metabolism (12) and deuterium MRS to follow infused deuterium-labeled-choline (13).MRS was also applied to investigate choline metabolism in normal organs (14,15). The content of the water-soluble choline metabolites in the brain was determined from the signal at 3.2 ppm of 1 H spectra. Although it was not possible to resolve this signal and identify the exact composition of the choline metabolites, its magnitude was indicative of brain tissue physiology and pathology, including brain tumors (4,16 -19). The uptake and metabolism of choline in the brain and the kidney were also investigated in vivo by 13 C and 2 H MRS, respectively, utilizing labeling of the trimethylamine moiety of choline (14,15). In these studies, as in 1 H-MRS, the choline sig...

Methionine‐dependence phenotype of tumors: Metabolite profiling in a melanoma model using L‐[methyl‐13C]methionine and high‐resolution magic angle spinning 1H–13C nuclear magnetic resonance spectroscopy

“…A betaine signal was found in tumors but was weakly labeled. This is consistent with the minor role of the methyl group recycling through the betaine pathway in tumors (29).…”

“…Using 13 C-labeled Cho in breast tumors, a value of 0.12 mol/h/g tissue ww was reported for the phosphorylation of Cho, the first step of the CDP-Cho pathway (29). Also a typical flux in tumors was reported to be ϳ0.08 mol/h/g tissue ww (38).…”

A hyperpolarized choline molecular probe for monitoring acetylcholine synthesis

“…Full Paper MRS of [1,2-13 C 2 ]choline had been used to monitor the conversion of choline to acetylcholine in live brain slices of rats (11), and to trace, in vivo, choline metabolism in breast cancer tumors implanted in nude mice (12). However, these measurements were carried out at very low temporal resolutions on the order of hours.…”

Estrogen Receptor α Promotes Breast Cancer by Reprogramming Choline Metabolism

“…Routing of Cho through its various metabolic pathways is cell and tissue specific (17). Following uptake of Cho, the intracellular metabolism of Cho is partitioned along two major pathways: (a) converted to PCho for the synthesis of phosphatidylcholine (PtdCho), a major constituent of cell membranes; or (b) oxidation to produce the methyl donor betaine (16).…”