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 citas
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- Diseño
- Estudio in vitro o de mecanismos (clasificado por nuestro filtro de IA)
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- Células o muestras de laboratorio
- Resultado principal
- Solo mecanismos
Quién lo pagó
- Financiación
- Financiación independiente
- Organización sin fines de lucro
- Cancer Research UK
- Organización sin fines de lucro
- British Heart Foundation
- Gobierno
- Medical Research Council
- Organización sin fines de lucro
- British Heart FoundationBritish Heart Foundation (BHF)
- Organización sin fines de lucro
- Cancer Research UKCancer Research UK (CRUK)
- Subvenciones
- 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)
Según 5 financiadores declarados.
Publicación
- Publicado
- 2019-03-18 · Mol Cancer Res · vol. 17 · número 7 · págs. 1531–1544
- Editorial
- American Association for Cancer Research
- Citado
- 30 citas · más que el 77% de estudios similares · 1.3× el promedio de su campo
- Referencias
- 50 trabajos
- Acceso
- Acceso abierto (copia en repositorio) · CC-BY-SA
- Áreas de investigación
- Cancer, Hypoxia, and Metabolism · Metabolism, Diabetes, and Cancer · Mitochondrial Function and Pathology
- Palabras clave
- 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 autores
- Alessandro Valli🇬🇧 · autor de correspondenciaNuffield Orthopaedic Centre; University of Oxford; MRC Weatherall Institute of Molecular Medicine
- Matteo Morotti🇬🇧University of Oxford; MRC Weatherall Institute of Molecular Medicine
- Christos E. Zois🇬🇧University of Oxford; MRC Weatherall Institute of Molecular Medicine
- Patrick K. Albers🇬🇧Centre for Human Genetics
- Tomoyoshi Soga🇯🇵Yamagata University; Keio University
- Katharina Feldinger🇬🇧University of Oxford; MRC Weatherall Institute of Molecular Medicine
- Román Fischer🇬🇧Nuffield Orthopaedic Centre
- Martin Frejno🇬🇧Nuffield Orthopaedic Centre
- Alan McIntyre🇬🇧University of Oxford; MRC Weatherall Institute of Molecular Medicine
- Esther Bridges🇬🇧University of Oxford; MRC Weatherall Institute of Molecular Medicine
- Syed Aleem Haider🇬🇧University of Oxford; MRC Weatherall Institute of Molecular Medicine
- Francesca Meteora Buffa🇬🇧University of Oxford; MRC Weatherall Institute of Molecular Medicine
- Dilair F. Baban🇬🇧Centre for Human Genetics
- Miguel Angel Rodriguez🇪🇸Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas; Universitat Rovira i Virgili
- Óscar Yanes🇪🇸Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas; Universitat Rovira i Virgili
- Hannah J. Whittington🇬🇧John Radcliffe Hospital; University of Oxford
- Hannah A. Lake🇬🇧John Radcliffe Hospital; University of Oxford
- Sevasti Zervou🇬🇧John Radcliffe Hospital; University of Oxford
- Craig A. Lygate🇬🇧John Radcliffe Hospital; University of Oxford
- Benedikt M. Kessler🇬🇧Nuffield Orthopaedic Centre
- Adrian L. Harris🇬🇧University of Oxford; MRC Weatherall Institute of Molecular Medicine
Resumen
El texto original del estudio, en el idioma en que se publicó.
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.
Resumen vía Europe PMC. Los derechos de autor siguen siendo de los autores o la editorial.
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