# Choline metabolism in cancer

Source: https://onco.cc/pathways/choline-metabolism-in-cancer/  
OnCo record `choline-metabolism-in-cancer` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

This KEGG map shows how cancer cells rewire the handling of choline, a nutrient used to build cell membranes, so that growth signals and membrane building feed each other. It matters because the resulting build-up of phosphocholine is visible on MR spectroscopy and PET scans and is one of the metabolic hallmarks of cancer.

## Summary

Abnormal choline metabolism is a metabolic hallmark associated with oncogenesis and tumour progression. KEGG map hsa05231 draws how oncogenic signalling through RAS-ERK and PI3K-AKT, together with transcription factors such as hypoxia-inducible factor 1 (HIF1), raises the expression and activity of choline cycle enzymes. Choline enters through transporters (CHT1, CTL1, OCT2), is phosphorylated by choline kinase alpha (CHKA) to phosphocholine, and is built into phosphatidylcholine by the Kennedy pathway. Phospholipases C and D and the phosphatidylcholine-specific enzymes then break membrane phosphatidylcholine back down to phosphocholine, diacylglycerol (DAG) and phosphatidic acid. These products act as second messengers: DAG activates protein kinase C and phosphatidic acid supports the RAS-RAF1-MAPK cascade and mTOR, so membrane turnover and growth signalling reinforce each other.

Glunde, Bhujwalla and Ronen, Nature Reviews Cancer, 2011 (doi:10.1038/nrc3162) review the field: the increase in total choline-containing compounds, and in particular the shift from glycerophosphocholine to phosphocholine, is seen across breast, prostate, brain and other cancers, is driven by CHKA over-expression and increased transporter activity, and can be imaged non-invasively by magnetic resonance spectroscopy and by choline PET. Response to targeted drugs (for example PI3K or MAPK inhibitors) lowers phosphocholine, making it a pharmacodynamic marker.

What can be done: choline kinase inhibitors have been developed and one (TCD-717) reached a phase 1 trial, but none is approved. Today the choline pathway is used as a read-out rather than a target: choline imaging helps diagnose and monitor tumours, and drugs against the upstream drivers (PI3K/AKT/mTOR inhibitors such as alpelisib, capivasertib and everolimus; MEK inhibitors such as trametinib) lower choline metabolite levels as they work.

## Fields

- Kind: Pathway
- Last checked: 2026-09-10
- Also known as: KEGG hsa05231; Choline metabolism in cancer
- Analogy: A building site where the bricks (choline) are also the walkie-talkies. The cell orders far more bricks than it needs for walls, keeps knocking finished walls down and rebuilding them, and every knocked-down brick sends a message telling the foreman to build faster. The pile of loose bricks is what the scanner sees.
- Interventions: Choline imaging (MR spectroscopy, choline PET) to diagnose tumours and read out response to therapy; Cut the upstream drivers: PI3K/AKT/mTOR inhibitors (alpelisib, capivasertib, everolimus) and MEK inhibitors (trametinib) lower phosphocholine as they act; Choline kinase alpha inhibitors (TCD-717 reached phase 1), no approved agent; HIF2 inhibition (belzutifan) where hypoxia signalling drives metabolic rewiring, approved in VHL-related and renal cancers

## Sources

- KEGG map hsa05231: https://www.kegg.jp/pathway/hsa05231
- Review: Choline metabolism in malignant transformation: https://doi.org/10.1038/nrc3162

## Connected records

- pathways: [Cancer metabolism](https://onco.cc/pathways/cancer-metabolism/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [VHL / HIF oxygen sensing](https://onco.cc/pathways/hif-vhl/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [HIF-2α](https://onco.cc/targets/hif2a/), [KRAS](https://onco.cc/targets/kras/), [mTOR](https://onco.cc/targets/mtor/)
- drugs: [Alpelisib](https://onco.cc/drugs/alpelisib/), [Belzutifan](https://onco.cc/drugs/belzutifan/), [Capivasertib](https://onco.cc/drugs/capivasertib/), [Everolimus](https://onco.cc/drugs/everolimus/), [Trametinib](https://onco.cc/drugs/trametinib/)
- key papers: [Choline metabolism in malignant transformation](https://onco.cc/key-papers/paper-glunde-nat-rev-cancer/)

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