Choline metabolism in malignant transformation

Key Points Some of the levels of metabolic intermediates that are generated in choline phospholipid metabolism, particularly phosphocholine (PCho) and total choline (tCho), are elevated in cancer, and can be used for non-invasive detection in cancer diagnosis and staging by using magnetic resonance spectroscopy (MRS) or positron emission tomography (PET). Several enzymes in choline metabolism, such as choline transporter-like protein 1 (CTL1), choline kinase-α (CHKα), CTP:phosphocholine cytidylyltransferase (CCT), phosphatidylcholine-specific phospholipase D (PC-PLD) and PC-PLC, are overexpressed and/or activated in cancer and can potentially be used as prognostic markers. Overexpression and activation of choline cycle enzymes are mediated by oncogenic signalling via pathways such as the RAS and PI3K–AKT pathways, and by transcription factors associated with oncogenesis such as hypoxia-inducible factor 1 (HIF1). Recent studies point to a reciprocal interaction between choline cycle enzymes and oncogenic signalling, where modulation of the enzymes can contribute to enhancing oncogenic signalling. The therapeutic response of tumours can be monitored non-invasively by MRS of the tCho signal because treatment with conventional chemotherapeutic agents results in a decrease of tCho levels in responding, but not in non-responding, tumours. Inhibition of oncogenic signalling pathways with targeted anticancer drugs results in altered choline-containing metabolite levels. Therefore, these metabolites could provide downstream metabolic readouts of the effective inhibition of these pathways. New molecularly targeted therapeutic opportunities arise from targeting choline cycle enzymes such as CHKα, which is currently being tested in Phase I clinical trials. Choline metabolism is commonly deregulated in cancer, leading to increased levels of choline metabolites. This Review discusses the deregulation of choline metabolism in cancer, its reciprocal interaction with oncogenic signalling and the possible clinical applications in diagnostics and therapy. Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, the modulation of enzymes that control anabolic and catabolic pathways causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These increased levels are associated with proliferation, and recent studies emphasize the complex