Tier 3 — preclinical

α-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer

Tran TQ, Hanse EA, Habowski AN, Li H, Gabra MI, Yang Y, Lowman XH, Ooi AM, Liao SY, Edwards RA, Waterman ML, Kong M
Nature Cancer 2020 1(3):345-358

Bibliography

PubMed
PMID 32832918
PubMed Central
PMC7442208
DOI
10.1038/s43018-020-0035-5
Funding
Supported by NIH grants R01CA183989 and R01GM132142 (M. Kong), R01CA17765 (M.L. Waterman and R.A. Edwards), U54CA217378 (M.L. Waterman), American Cancer Society grant RSG-16-085-01-TBE (M. Kong), American Cancer Society fellowship PFDDC-132846 (E.A. Hanse), NSF DGE-1321846 and NIH T32CA009054 (A.N. Habowski), with core-facility support from NIH P30CA062203.
Competing interests
The authors declared no competing interests.

Study snapshot

DesignMechanistic colorectal-cancer organoid and in-vivo tumor-model study.
ModelAPC-mutant intestinal organoids, patient-derived colorectal cancer organoids and mouse tumor models.
SampleMultiple organoid and mouse experiments; group sizes varied by model.
InterventionExogenous AKG supplementation under glutamine-restricted and tumor-model conditions.
DurationStudy-specific organoid and in-vivo tumor protocols.
EndpointsWnt signaling; Cellular differentiation; DNA and histone methylation; Tumor growth; Survival in mouse tumor models

What the study showed, in plain terms

This Nature Cancer paper shows why AKG and cancer cannot be reduced to a simple 'feeds tumors' or 'prevents cancer' claim.

In colorectal-cancer models, low glutamine reduced intracellular AKG and enhanced Wnt-driven stemness. Restoring AKG promoted differentiation, suppressed Wnt signaling and restricted tumor growth in multiple preclinical models.

The work is mechanistically strong but preclinical; it does not demonstrate that oral Ca-AKG prevents or treats colorectal cancer in humans.

Key findings

  • AKG reversed low-glutamine-induced Wnt hyperactivation and stemness.
  • AKG promoted epigenetic changes associated with differentiation.
  • AKG restricted tumor growth and improved survival in several preclinical colorectal-cancer models.

What this study can and cannot tell us

  • Preclinical cancer models only.
  • Tumor-model AKG exposure is not equivalent to oral Ca-AKG supplementation in healthy people.
  • Cancer metabolism is context-specific; these findings should not be generalized across tumor types.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology