Choline metabolism in malignant transformation

Abstract

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 reciprocal interactions between oncogenic signalling and choline metabolism. Because choline-containing compounds are detected by non-invasive magnetic resonance spectroscopy (MRS), increased levels of these compounds provide a non-invasive biomarker of transformation, staging and response to therapy. Furthermore, enzymes of choline metabolism, such as choline kinase, present novel targets for image-guided cancer therapy.

Figure 1. Overview of deregulated choline metabolism in cancer

Magnetic resonance spectroscopy (MRS) studies with cells, animal models and human studies have revealed deregulated choline metabolism in cancer. Oncogenic pathways (shown in light red), tumour suppressor pathways (dark red) and molecules that are associated with choline metabolism (green) in cancer are shown in the upper circle. These studies have led to the use of MRS for cancer detection and for following the treatment-induced changes in total choline-containing compounds (tCho) to determine response to therapy. The association of choline metabolism with cancer has also led to the development of inhibitors that target enzymes in the pathway, and a Phase I clinical trial with a choline kinase-α (CHKα) inhibitor has been initiated. COX2, cyclooxygenase 2; HIF1, hypoxia-inducible factor 1.

Figure 2. Control of choline metabolism by oncogenic signalling pathways

Oncogenic signalling pathways (part a) that interact with the choline metabolic pathway (part b) are shown. Grey arrows represent the choline metabolism pathway, proteins in grey catalyse the reaction that is depicted by the corresponding grey arrow. Dashed grey arrows indicate the regulation of enzyme activity in the choline metabolism pathway. Black arrows indicate connections to the oncogenic signalling pathways shown in part a. Solid black arrows indicate increased or decreased enzyme activity, dashed black arrows indicate increased gene transcription. AP1, activator protein 1; CHK, choline kinase; CHPT1, diacylglycerol cholinephosphotransferase 1; CCT, CTP:phosphocholine cytidylyltransferase; DAG, diacylglycerol; FA, fatty acid; GPC, glycerophosphocholine; HIF1, hypoxia-inducible factor 1; JNK, JUN N-terminal kinase; PC-PLC, phosphatidylcholine-specific phospholipase C; PC-PLD, phosphatidylcholine-specific phospholipase D; PLA2, phosphatidylcholine-specific phospholipase A2; PCho, phosphocholine; PtdCho, phosphatidylcholine; RALGDS, RAL GTPase guanine nucleotide dissociation stimulator; RTK, receptor tyrosine kinase; SREBP, sterol regulatory element binding protein.

Figure 3. The major enzymes involved in choline phospholipid metabolism in the cell

Enzymes shown in grey indicate active choline cycle enzymes, which are shown in the organelle in which they are active. Enzymes shown in dark blue indicate the location of choline cycle enzymes that are deactivated by translocation to a different organelle. Black arrows represent the choline metabolism pathway, proteins in grey catalyse the reaction that is depicted by the corresponding black arrow and choline cycle metabolites are shown in bold. Dashed grey arrows show translocation to different subcellular locations, which can deactivate (dark blue) or activate (grey) the enzyme. CCT, CTP: phospho-choline cytidylyltransferase; CDP-Cho, cytidine diphosphate-choline; CHKα, choline kinase-α; Cho_e, extracellular free choline; Cho_i, intracellular free choline; CHPT1, diacylglycerol cholinephosphotransferase 1; CMP, cytidine monophosphate; CTP, cytidine triphosphate; FA, fatty acid; GPC, glycerophosphocholine; GPC-PDE, glycerophospho-choline phosphodiesterase; Gro-3-P, glycerol-3-phosphate; Lyso-PLA1, lyso-phospholipase A1; PCho, phosphocholine; PC-PLC, phosphatidylcholine-specific phospholipase C; PC-PLD, phosphatidylcholine-specific phospholipase D; PLA2, cytoplasmic phosphatidylcholine-specific phospholipase A2; PP_i, diphosphate.

Timeline. Deregulated choline metabolism in cancer

CHKα, choline kinase-α; HSP90, heat shock protein 90; MRS, magnetic resonance spectroscopy; PCho, phosphocholine; PET, positron emission tomography; PEtn, phosphoethanolamine; PLD1, phospholipase D1; PME, phosphomonoester; PtdCho, phosphatidylcholine; RALGDS, RAL GTPase guanine nucleotide dissociation stimulator; tCho, total choline-containing compounds.