High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells
Abstract
Alterations in metabolic activities are cancer hallmarks that offer a wide range of new therapeutic opportunities. Here we decipher the interplay between mTORC1 activity and glucose metabolism in acute myeloid leukemia (AML). We show that mTORC1 signaling that is constantly overactivated in AML cells promotes glycolysis and leads to glucose addiction. The level of mTORC1 activity determines the sensitivity of AML cells to glycolysis inhibition as switch-off mTORC1 activity leads to glucose-independent cell survival that is sustained by an increase in mitochondrial oxidative phosphorylation. Metabolic analysis identified the pentose phosphate pathway (PPP) as an important pro-survival pathway for glucose metabolism in AML cells with high mTORC1 activity and provided a clear rational for targeting glucose-6-phosphate dehydrogenase (G6PD) in AML. Indeed, our analysis of the cancer genome atlas AML database pinpointed G6PD as a new biomarker in AML, as its overexpression correlated with an adverse prognosis in this cohort. Targeting the PPP using the G6PD inhibitor 6-aminonicotinamide induces in vitro and in vivo cytotoxicity against AML cells and synergistically sensitizes leukemic cells to chemotherapy. Our results demonstrate that high mTORC1 activity creates a specific vulnerability to G6PD inhibition that may work as a new AML therapy.
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High mTORC1 activity in cancer cells promotes aerobic glycolysis and drives glucose addiction.
“Accordingly, high mTORC1 activity in cancer cells promotes aerobic glycolysis and drives glucose addiction162,163”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [162]
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Glutamine reliance in cell metabolism
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- Authors
- Poulain, L., Sujobert, P., Zylbersztejn, F., Barreau, S., Stuani, L., Lambert, M., Palama, T. L., Chesnais, V, Birsen, R., Vergez, F., Farge, T., Chenevier-Gobeaux, C., Fraisse, M., Bouillaud, F., Debeissat, C., Herault, O., Récher, C., Lacombe, C., Fontenay, M., Mayeux, P., Maciel, T. T., Portais, J.-C., Sarry, J.-E., Tamburini, J., Bouscary, D., & Chapuis, N.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Toulouse III - Paul Sabatier (FR)
- Corresponding author
- Bouscary, D
- Chapuis, N
- ORCID
- Venue
- Leukemia
- Published
- 2017-03-10
- Volume
- 31
- Issue
- 11
- Pages
- 2326-2335
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- OpenAlex
- W2592973432
- Cited by
- 145
- References
- 58
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 17 · 2023: 18 · 2022: 21 · 2021: 28 · 2020: 24 · 2019: 17 · 2018: 6 · 2017: 1
- FWCI
- 4.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Leukemia (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-11-INBS-0010)
- Institut National Du Cancer
- Institute of Cancer Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- acute myeloid leukemia, mTORC1 signaling, glycolysis, glucose-6-phosphate dehydrogenase, 6-aminonicotinamide, pentose phosphate pathway, oxidative phosphorylation, cancer metabolism, metabolic vulnerability, chemosensitization, prognostic factors, glucose metabolism
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Glucose, Glucosephosphate Dehydrogenase, Glycolysis, Humans, Oxidative Phosphorylation, Leukemia, Myeloid, Acute
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