دورية أكاديمية
Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism.
| العنوان: | Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism. |
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| المؤلفون: | Valli A; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. alevalli14@gmail.com alessandro.valli@cardiologicomonzino.it.; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Morotti M; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Zois CE; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Albers PK; The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom., Soga T; Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan., Feldinger K; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Fischer R; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Frejno M; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., McIntyre A; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Bridges E; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Haider S; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Buffa FM; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Baban D; The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom., Rodriguez M; Metabolomics Platform, IISPV, Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, Spain.; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders-CIBERDEM, Madrid, Spain., Yanes O; Metabolomics Platform, IISPV, Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, Spain.; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders-CIBERDEM, Madrid, Spain., Whittington HJ; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom., Lake HA; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom., Zervou S; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom., Lygate CA; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom., Kessler BM; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Harris AL; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. |
| المصدر: | Molecular cancer research : MCR [Mol Cancer Res] 2019 Jul; Vol. 17 (7), pp. 1531-1544. Date of Electronic Publication: 2019 Mar 18. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101150042 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3125 (Electronic) Linking ISSN: 15417786 NLM ISO Abbreviation: Mol Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, c2002- |
| مواضيع طبية MeSH: | Colonic Neoplasms/*genetics , Energy Metabolism/*genetics , Glucose Transport Proteins, Facilitative/*genetics , Hypoxia-Inducible Factor 1, alpha Subunit/*genetics, Colonic Neoplasms/pathology ; Creatine/genetics ; Creatine/metabolism ; Fructose-Bisphosphate Aldolase/genetics ; Glucose/metabolism ; Glycolysis/genetics ; HCT116 Cells ; Humans ; Spheroids, Cellular/metabolism ; Tumor Hypoxia/genetics |
| مستخلص: | 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. (©2019 American Association for Cancer Research.) |
| معلومات مُعتمدة: | 23969 United Kingdom CRUK_ Cancer Research UK; MR/P010334/1 United Kingdom MRC_ Medical Research Council; RG/18/12/34040 United Kingdom BHF_ British Heart Foundation; C602/A18974 United Kingdom CRUK_ Cancer Research UK; RG/13/8/30266 United Kingdom BHF_ British Heart Foundation; 18974 United Kingdom CRUK_ Cancer Research UK |
| المشرفين على المادة: | 0 (Glucose Transport Proteins, Facilitative) 0 (HIF1A protein, human) 0 (Hypoxia-Inducible Factor 1, alpha Subunit) 0 (SLC2A14 protein, human) EC 4.1.2.13 (Fructose-Bisphosphate Aldolase) IY9XDZ35W2 (Glucose) MU72812GK0 (Creatine) |
| تواريخ الأحداث: | Date Created: 20190320 Date Completed: 20200501 Latest Revision: 20240210 |
| رمز التحديث: | 20240210 |
| DOI: | 10.1158/1541-7786.MCR-18-0315 |
| PMID: | 30885992 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1557-3125 |
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| DOI: | 10.1158/1541-7786.MCR-18-0315 |