ReviewThe role of choline in prostate cancer
Highlights
► Choline is an essential nutrient with a potential role in prostate cancer. ► Choline uptake and turn over are increased in cancer cells. ► Choline is a source of methyl groups that contribute to carcinogenesis. ► Several enzymes in choline metabolism are overexpressed in cancer. ► Hormones and hypoxia contribute to altered choline metabolism in prostate cancer.
Introduction
Choline is an essential nutrient [1]. The main dietary sources of choline are beef and chicken liver, eggs, wheat germ, and dried soybeans [2]. The recommended daily requirements for choline have been set to 550 mg/day for men and 425 mg/day for non-pregnant women [1]. Choline is necessary for the synthesis of acetylcholine, membrane and signaling phospholipids, and as a source of methyl groups [3].
Dietary intake is not the only source of choline, since a considerable amount of this compound can be produced de novo from phosphatidylethanolamine via phosphatidylcholine (PtdCho). Pathological changes in the liver and muscles were observed in 77% of men on a diet that was poor in choline [4]. These observations suggest that the endogenous synthesis of choline is not sufficient to meet the daily requirements. Genetic variations of choline dehydrogenase and phosphatidylethanolamine N-methyltransferase can influence the dietary requirements for choline [5], [6].
Choline metabolism has been linked to malignant transformation characterized by a higher proliferation rate and increased phosphocholine (PCho) and other choline-containing compounds [7], [8]. Inducing the proliferation of normal cells by growth hormones was not associated with an increase in PCho and total choline levels in one study [8]. Therefore, the role of choline in cancer goes beyond the expected higher requirements caused by cell division and the increased synthesis rate of new cell membranes. Cancer cells exhibit an abnormal choline phospholipid metabolism [8], [9], [10]. The extensive alterations in choline metabolism in malignant transformation have been shown to be related to the expression of enzymes involved in this pathway [7]. Moreover, aberrant choline metabolism might be related to malignant transformation via genetic and epigenetic dysregulations [11], [12].
Few studies observed a positive association between the dietary choline intake or plasma concentration of choline and the risk of some types of cancer [13], [14], including PCA [15]. Other studies observed no significant relationship [16], [17]. Prostate cancer (PCA) accounts for 14% of all newly diagnosed cancer cases worldwide in 2008 [18]. The rising incidence rate of PCA reflects in part the widespread screening for prostate-specific antigen (PSA). Risk factors such as age, ethnicity, family history, lifestyle, and androgens are also discussed in relation to the PCA risk [19], [20]. Beyond enhanced lipid biosynthesis, altered choline phospholipid metabolism is one of the characteristic features of PCA [21], [22]. Dietary choline, as a major source of choline, phospholipids, and methyl groups might be a potential modifiable risk factor or risk marker for PCA.
The role of choline phospholipid metabolism in cell function and signaling makes it one important target candidate for tumor treatment or prevention. This review summarizes the current knowledge regarding the implications of choline in carcinogenesis and discusses the potential usage of choline and choline phospholipid metabolites as prognostic biomarkers in patients with PCA.
Section snippets
The role of choline as a methyl donor
The proportional distribution of dietary or endogenous choline between phospholipids and the methylation pathways has not been studied much. Choline is oxidized to betaine via two-step irreversible reactions mediated by choline dehydrogenase and betaine aldehyde dehydrogenase. Betaine homocysteine methyl transferase mediates the transfer of the methyl group from betaine to homocysteine to produce methionine that is in turn converted into S-adenosylmethionine (SAM), the universal methyl donor (
The role of choline in phospholipid metabolism
Choline is utilized for the de novo synthesis of PtdCho via the Kennedy pathway (also called CDP-choline pathway) (Fig. 2) [28]. The Kennedy pathway involves three reactions. In the first step, choline kinase (CHK) catalyzes the phosphorylation of choline into PCho. This reaction can be a rate-limiting step for PtdCho biosynthesis [29]. CHK has three isoforms (CHKα1, CHKα2, and CHKβ) all of them have choline kinase activity [30]. The second reaction in the Kennedy pathway is catalyzed by the
Choline uptake in normal and PCA cells
The plasma concentrations of free choline are around 10 μmol/L [1], [3]. These concentrations are maintained via dietary choline and endogenous synthesis. Dietary choline is absorbed in the intestine [43]. The quaternary amine choline is a charged hydrophilic cation, which needs specific transporters to pass the membrane lipid barrier [44]. Choline transporters mediate the cellular uptake and the transport is the rate limiting step for the synthesis of PCho [7]. Four choline transporters have
Choline metabolism in relation to oncogenic signaling, hormone therapy, and hypoxia
Molecules derived by the breakdown of choline-containing phospholipids such as DAG and PCho can act as second messengers in mitogenic signal transduction pathways. Other molecules like lyso-phosphatidic acid can activate enzymes involved in choline metabolism such as PLD [38], [39], [41]. Moreover, phosphatidic acid, the precursor of lyso-phosphatidic acid and DAG, has regulatory properties that are implicated in oncogenic signaling and activation of enzymes involved in choline metabolism [7].
Choline phospholipid metabolites as prognostic markers in PCA
Accurate clinical staging of PCA is very important for the management of the disease and optimization of the therapy regimen. Total choline levels in prostate tissue have been shown to be positively related to the Gleason score and tumor aggressiveness in patients with PCA [56]. Several PET/CT techniques that depend on studying the uptake of radiolabelled choline (11C-choline) in tumor cells have shown that 11C-choline might be helpful in monitoring the recurrence of PCA, but not for initial
Conclusion
Choline might affect PCA risk via several mechanisms, including DNA methylation or phospholipid metabolism. Alternatively, choline metabolism in PCA might be dysregulated in order to meet the tumor requirements for phospholipids and methyl groups. Common polymorphisms in genes involved in choline metabolism such as phosphatidylethanolamine N-methyltransferase and choline dehydrogenase might interact with choline metabolism and affect its requirements. Tissues might vary in terms of choline
Conflict of interest
The authors have no conflict of interests regarding the content of this article.
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