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Adaptation to Hif1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism

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Adaptation to Hif1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism Published OnlineFirst March 18, 2019; DOI: 10.1158/1541-7786.MCR-18-0315 Metabolism Molecular Cancer Research Adaptation to HIF1a Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism Alessandro Valli1,2, Matteo Morotti1, Christos E. Zois1, Patrick K. Albers3, Tomoyoshi Soga4, Katharina Feldinger1, Roman Fischer2, Martin Frejno2, Alan McIntyre1, Esther Bridges1, Syed Haider1, Francesca M. Buffa1, Dilair Baban3, Miguel Rodriguez5,6, Oscar Yanes5,6, Hannah J. Whittington7, Hannah A. Lake7, Sevasti Zervou7, Craig A. Lygate7, Benedikt M. Kessler2, and Adrian L. Harris1 Abstract Hypoxia-inducible factor 1a is a key regulator of the than phosphofructokinase. Furthermore, glucose uptake hypoxia response in normal and cancer tissues. It is well could be maintained in hypoxia through upregulation of recognized to regulate glycolysis and is a target for therapy. GLUT14, not previously recognized in this role. Finally, However, how tumor cells adapt to grow in the absence of there was a marked adaptation and change of phospho- HIF1a is poorly understood and an important concept to creatine energy pathways, which made the cells susceptible understand for developing targeted therapies is the flexi- to inhibition of creatine metabolism in hypoxic condi- bility of the metabolic response to hypoxia via alternative tions. Overall, our studies show a complex adaptation to pathways. We analyzed pathways that allow cells to survive hypoxia that can bypass HIF1a, but it is targetable and it hypoxic stress in the absence of HIF1a,usingtheHCT116 provides new insight into the key metabolic pathways colon cancer cell line with deleted HIF1a versus control. involved in cancer growth. Spheroids were used to provide a 3D model of metabolic gradients. We conducted a metabolomic, transcriptomic, Implications: Under hypoxia and HIF1 blockade, cancer cells and proteomic analysis and integrated the results. These adapt their energy metabolism via upregulation of the showed surprisingly that in three-dimensional growth, GLUT14 glucose transporter and creatine metabolism provid- a key regulatory step of glycolysis is Aldolase A rather ing new avenues for drug targeting. Introduction conditions such as hypoxia, acidic pH, and a nutrient-poor microenvironment (1). Highly proliferating cancer cells must increase the import of Warburg first described the increase of oxidation of glucose nutrients and adopt a metabolic program that fulfils energetic, into lactate in cancer cells (2). Although yielding less ATP than redox, and biosynthetic requirements for increasing cell mass. OXPHOS, glycolysis is utilized predominantly by cancer cells and Metabolic flexibility is acquired through genetic and nonge- provides a more rapid response to the high energy demand of netic factors that allow tumors to grow in altered biochemical rapidly proliferating cancer cells (3). In hypoxia, this regulation represents the predominant way to produce ATP, even for normal cells (1). Although many solid tumors demonstrate the Warburg 1Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United 2 fi effect, some, such as prostate cancer, do not (4). Virus-infected Kingdom. Target Discovery Institute, Nuf eld Department of Medicine, Uni- þ versity of Oxford, Oxford, United Kingdom. 3The Wellcome Trust Centre for cells show increased glucose metabolism and CD4 T-cell growth Human Genetics, University of Oxford, Oxford, United Kingdom. 4Institute for is characterized by a high synthesis of ATP and biosynthetic Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan. 5Metabo- reactions (cell membrane and DNA biosynthesis). These observa- lomics Platform, IISPV, Department of Electronic Engineering, Universitat Rovira tions show that uncoupling glycolysis from OXPHOS can offer a 6 i Virgili, Tarragona, Spain. Spanish Biomedical Research Center in Diabetes and metabolic solution adequately beneficial for the high energy Associated Metabolic Disorders-CIBERDEM, Madrid, Spain. 7Division of Cardio- vascular Medicine, Radcliffe Department of Medicine, University of Oxford, demand while maintaining redox balance and biosynthetic Oxford, United Kingdom. requirements (5–7). Similarly, reprogramming of cancer metab- olism activates distinct pathways in which oncogenic mutations Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). convey downstream signals to directed prometabolic traits (1). Adaptation to the hypoxic tumor microenvironment is driven B.M. Kessler and A.L. Harris are the co-senior authors of this article. by hypoxia-inducible factors HIF1a and HIF2a that induce a Corresponding Author: Alessandro Valli, University of Oxford, Oxford OX3 9DS, distinct transcriptional program (8). HIF1a regulates numerous United Kingdom. Phone: 4418-6522-2420; Fax: 4418-6522-2431; E-mail: metabolic genes, especially those involved in glycolysis and [email protected] and [email protected] related auxiliary processes (9). doi: 10.1158/1541-7786.MCR-18-0315 Because of the importance of HIF1 in tumor growth and the Ó2019 American Association for Cancer Research. potential of HIF1a as target, we investigated how a cell line www.aacrjournals.org OF1 Downloaded from mcr.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst March 18, 2019; DOI: 10.1158/1541-7786.MCR-18-0315 Valli et al. deleted for HIF1a could survive in hypoxia. We studied the the increase in absorbance at 412 nm over 1 minute as a result of HCT116 colorectal cancer cell line wild-type (WT) and HIF1a 5-thio-2-nitrobenzoate (TNB2-) production. The assay was per- knockout (KO) under hypoxic conditions and analyzed transcrip- formed in duplicate and results were normalized by protein tomics, proteomics, metabolomics, and fluxomics. We integrated concentration. the multi-omics data to construct a map of hypoxic colorectal cancer cell energy metabolism. Our results show for the first time upregulation of glucose transporter type 14 (GTR14) to maximize Results nutrient uptake and an important role for creatine (Cr) energy HIF1a regulates hypoxic spheroid cancer growth pathways to sustain multidimensional growth under hypoxic We cultured WT and KO HCT116 cells as spheroids (WTs and conditions. KOs) for 72 hours, generating a hypoxic inner mass, and evaluated their morphology at three time points (72.5, 76, and 96 hours). Immunostaining of WTs and KOs spheroids at 96 hours showed Materials and Methods key differences in hypoxic adaptation. Pimonidazole (PIMO)- Cell culture positive staining, in both WTs and KOs, confirmed the presence of Cell lines were available from Clare Hall Laboratories hypoxic areas, and carbonic anhydrase 9 (CA9; HIF1a-target) (HCT116), or were a kind gift from Prof Walter Bodmer (Weath- positive stain in WTs demonstrated the presence of hypoxia and erall Institute of Molecular Medicine, Oxford, United Kingdom; HIF1a stabilization. In contrast, CA9 staining was absent in KOs, DLD-1, Ls174T). Cell line authentication was carried out by short demonstrating successful HIF1a knockout. Necrosis and cell tandem repeat analyses (LGC Standards) 6 months prior to the first death, as measured by H&E staining, was more pronounced in submission of the manuscript. Cells were cultured as described WTs than in KOs (Fig. 1A). previously, unless different conditions were specified (10). We evaluated differences in growth of WTs and KOs (Fig. 1B). HCT116 WTs and KOs proliferated over 24 hours, with a higher Enzyme activity assay rate in WTs (top). WTs volume was overall significantly bigger WT and KO HCT116 cells were cultivated at either 21% O2 or than that of KOs cells with no marked changes over time (middle). 1% O2 for 24 hours. Cells were collected, pelleted, and suspended Cell spheroid density (number of cells per spheroid/spheroid in 1 mL of ice-cold buffer (0.08 mmol/L K2HPO4, 1 mmol/L volume) showed a significant increased over time in both WTs EGTA, 0.02 mmol/L KH2PO4, and 1 mmol/L b-mercaptoethanol) and KOs and was more pronounced in KOs at 96 hours (bottom). while under experimental conditions. Samples were vortexed and 150 mL aliquots removed for determination of protein by the HIF1a metabolic effects in cancer spheroids Lowry method. A final concentration of 0.1% v/v Triton X-100 was Because WTs and KOs grow unequally, we optimized the added to permeabilize cells. Samples were stored on ice for at least formation of WTs and KOs with a comparable cell number, 30 minutes to allow precipitation and the supernatant was used morphology, volume, and diameter, which enabled the investi- for all enzyme activity measurements. gation of hypoxic gradients at the studied time points (72.5, 76, and 96 hours; data not shown). We measured 26 metabolites of Total creatine kinase activity six metabolic pathways: glycogen (GLG), glycolysis (GLY), TCA Twenty microliters of 1:5 (in ice buffer) diluted sample super- cycle, ATP, Cr, and redox metabolism (Fig. 1C). GLG metabolic natant was incubated with 1 mL of creatine kinase (CK)-NAC intermediates show a general decrease over time in both WTs and reagent (Thermo Fisher Scientific) at 30C. After 3-minute lag KOs. Glycolysis and Cr metabolic products accumulated mostly time, CK activity was quantified spectrophotometrically by mea- in WTs. TCA cycle metabolites did not show a defined trend, but suring the increase in absorbance at 340 nm over 2 minutes as a generally appeared to be more elevated in WTs at 96
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