Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism
Valli A, Morotti M, Zois CE, Albers PK, Soga T, Feldinger K, Fischer R, Frejno M, McIntyre A, Bridges E, Haider S, Buffa FM, Baban D, Rodriguez M, Yanes O, Whittington HJ, Lake HA, Zervou S, Lygate CA, Kessler BM, Harris AL
Molecular cancer research : MCR · 26 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- In vitro/mechanistic study (classified by our AI screen)
- Studied in
- Cells or lab samples
- Main outcome
- Mechanisms only
Who paid for it
- Funding
- Independent funding
- Nonprofit
- Cancer Research UK
- Nonprofit
- British Heart Foundation
- Government
- Medical Research Council
- Nonprofit
- British Heart FoundationBritish Heart Foundation (BHF)
- Nonprofit
- Cancer Research UKCancer Research UK (CRUK)
- Grants
- British Heart Foundation (RG/13/8/30266); British Heart Foundation (RG/18/12/34040); Medical Research Council (MR/P010334/1); Cancer Research UK (C602/A18974); Cancer Research UK (23969); Cancer Research UK (18974)
Based on 5 listed funder(s).
Publication
- Published
- 2019-03-18 · Mol Cancer Res · vol. 17 · issue 7 · pp. 1531–1544
- Publisher
- American Association for Cancer Research
- Cited
- 30 citations · more than 77% of similar papers · 1.3× the field average
- References
- 50 works
- Access
- Open access (repository copy) · CC-BY-SA
- Research areas
- Cancer, Hypoxia, and Metabolism · Metabolism, Diabetes, and Cancer · Mitochondrial Function and Pathology
- Keywords
- Downregulation and upregulation, Cancer research, Adaptation (eye), Metabolic adaptation, Cancer, Hypoxia (environmental), Biology, Cellular adaptation, Metabolism, Gene, Chemistry, Genetics, Biochemistry, Neuroscience
- MeSH
- hct116 cells, spheroids, cellular, humans, colonic neoplasms, creatine, fructose-bisphosphate aldolase, glucose, energy metabolism, glycolysis, glucose transport proteins, facilitative, hypoxia-inducible factor 1, alpha subunit, tumor hypoxia
21 authors
From GB, JP, ES
- Alessandro Valli · correspondingNuffield Orthopaedic Centre; University of Oxford; MRC Weatherall Institute of Molecular Medicine
- Matteo MorottiUniversity of Oxford; MRC Weatherall Institute of Molecular Medicine
- Christos E. ZoisUniversity of Oxford; MRC Weatherall Institute of Molecular Medicine
- Patrick K. AlbersCentre for Human Genetics
- Tomoyoshi SogaYamagata University; Keio University
- Katharina FeldingerUniversity of Oxford; MRC Weatherall Institute of Molecular Medicine
Abstract
Hypoxia-inducible factor 1α is a key regulator of the hypoxia response in normal and cancer tissues. It is well recognized to regulate glycolysis and is a target for therapy. However, how tumor cells adapt to grow in the absence of HIF1α is poorly understood and an important concept to understand for developing targeted therapies is the flexibility of the metabolic response to hypoxia via alternative pathways. We analyzed pathways that allow cells to survive hypoxic stress in the absence of HIF1α, using the HCT116 colon cancer cell line with deleted HIF1α versus control. Spheroids were used to provide a 3D model of metabolic gradients. We conducted a metabolomic, transcriptomic, and proteomic analysis and integrated the results. These showed surprisingly that in three-dimensional growth, a key regulatory step of glycolysis is Aldolase A rather than phosphofructokinase. Furthermore, glucose uptake could be maintained in hypoxia through upregulation of GLUT14, not previously recognized in this role. Finally, there was a marked adaptation and change of phosphocreatine energy pathways, which made the cells susceptible to inhibition of creatine metabolism in hypoxic conditions. Overall, our studies show a complex adaptation to hypoxia that can bypass HIF1α, but it is targetable and it provides new insight into the key metabolic pathways involved in cancer growth. IMPLICATIONS: Under hypoxia and HIF1 blockade, cancer cells adapt their energy metabolism via upregulation of the GLUT14 glucose transporter and creatine metabolism providing new avenues for drug targeting.
Abstract via Europe PMC. Copyright remains with the authors or publisher.
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