MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells
Open accessAbstract
The anti-diabetic drug metformin targets pancreatic cancer stem cells (CSCs), but not their differentiated progenies (non-CSCs), which may be related to distinct metabolic phenotypes. Here we conclusively demonstrate that while non-CSCs were highly glycolytic, CSCs were dependent on oxidative metabolism (OXPHOS) with very limited metabolic plasticity. Thus, mitochondrial inhibition, e.g., by metformin, translated into energy crisis and apoptosis. However, resistant CSC clones eventually emerged during treatment with metformin due to their intermediate glycolytic/respiratory phenotype. Mechanistically, suppression of MYC and subsequent increase of PGC-1α were identified as key determinants for the OXPHOS dependency of CSCs, which was abolished in resistant CSC clones. Intriguingly, no resistance was observed for the mitochondrial ROS inducer menadione and resistance could also be prevented/reversed for metformin by genetic/pharmacological inhibition of MYC. Thus, the specific metabolic features of pancreatic CSCs are amendable to therapeutic intervention and could provide the basis for developing more effective therapies to combat this lethal cancer.
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High glycolytic flux is required to maintain upregulated PGD metabolism, and this is maintained in part through suppression of TXNIP transcription.
“High glycolytic flux is required to maintain upregulated PGD metabolism, and this in maintained in part through suppression of thioredoxin-interacting protein (TXNIP) transcription243.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [243]
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- Authors
- Sancho, P., Burgos-Ramos, E., Tavera, A., Bou Kheir, T., Jagust, P., Schoenhals, M., Barneda, D., Sellers, K., Campos-Olivas, R., Graña, O., Viera, C. R., Yuneva, M., Sainz, B., & Heeschen, C.
- Affiliations
- Queen Mary University of London (GB)
- Spanish National Cancer Research Centre (ES)
- Corresponding author
- Sancho, Patricia
- Heeschen, Christopher
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 22
- Issue
- 4
- Pages
- 590-605
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W1892036645
- Cited by
- 722
- References
- 44
- Citations by year
- 2026: 36 · 2025: 51 · 2024: 60 · 2023: 72 · 2022: 79 · 2021: 88 · 2020: 94 · 2019: 79 · 2018: 65 · 2017: 51 · 2016: 41 · 2015: 5
- FWCI
- 17.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- RUIdeRA - Institutional University Repository (University of Castilla-La Mancha) (submittedVersion, other-oa)
- Funders
- Francis Crick Institute (10223)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- pancreatic cancer stem cells, c-Myc, PGC-1α, metformin, oxidative phosphorylation, glycolysis, metabolic plasticity, drug resistance, mitochondrial reactive oxygen species, menadione, apoptosis, energy crisis, cancer metabolism
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, AC133 Antigen, Animals, Antineoplastic Agents, Glycoproteins, Humans, Metformin, Mice, Nude, Mitochondria, Oxidative Phosphorylation, Pancreatic Neoplasms, Peptides, Phenotype, Transcription Factors, Tumor Cells, Cultured, Neoplastic Stem Cells, Antigens, CD, Gene Library, Proto-Oncogene Proteins c-myc, Reactive Oxygen Species, Drug Resistance, Neoplasm, Vitamin K 3, RNA Interference, Mice
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