Regulation of glucose uptake in lymphoma cell lines by c-MYC- and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viability
Abstract Background Changes in glucose and energy metabolism contribute to the altered phenotype of cancer cells and are the basis for positron emission tomography with 18F-fluoro-2-deoxy-d-glucose (FDG) to visualize tumors in vivo. The molecular background of the enhanced glucose uptake and its reg...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-07-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12967-017-1258-9 |
| _version_ | 1818893575842168832 |
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| author | Martina Broecker-Preuss Nina Becher-Boveleth Andreas Bockisch Ulrich Dührsen Stefan Müller |
| author_facet | Martina Broecker-Preuss Nina Becher-Boveleth Andreas Bockisch Ulrich Dührsen Stefan Müller |
| author_sort | Martina Broecker-Preuss |
| collection | DOAJ |
| description | Abstract Background Changes in glucose and energy metabolism contribute to the altered phenotype of cancer cells and are the basis for positron emission tomography with 18F-fluoro-2-deoxy-d-glucose (FDG) to visualize tumors in vivo. The molecular background of the enhanced glucose uptake and its regulation in lymphoma cells is not fully clarified and may provide new possibilities to reverse the altered metabolism. Thus in this study we investigated regulation of glucose uptake by different signaling pathways. Furthermore, the effect of the glucose analog 2-deoxy-d-glucose (2-DG) alone and in combination with other inhibitors on cell survival was studied. Methods An FDG uptake assay was established and uptake of FDG by lymphoma cells was determined after incubation with inhibitors of the c-MYC and the PI3K signalling pathways that are known to be activated in lymphoma cells and able to regulate glucose metabolism. Inhibitors of MAPK signalling pathways whose role in altered metabolism is still unclear were also investigated. Expression of mRNAs of the glucose transporter 1 (GLUT1), hexokinase 2 (HK2), glucose-6-phosphatase (G6Pase) and lactate dehydrogenase A (LDHA) and of the glucose metabolism-regulating micro RNAs (miRNA) miR21, -23a, -133a, -133b, -138-1 and -143 was determined by RT-PCR. Cell viability was analysed by MTT assay. Results Treatment with the c-MYC inhibitor 10058-F4 and inhibitors of the PI3K/mTOR pathway diminished uptake of FDG in all three cell lines, while inhibition of MAPK pathways had no effect on glucose uptake. Expression of glycolysis-related genes and miRNAs were diminished, although to a variable degree in the three cell lines. The c-MYC inhibitor, the PI3K inhibitor LY294002, the mTOR inhibitor Rapamycin and 2-DG all diminished the number of viable cells. Interestingly, in combination with 2-DG, the c-MYC inhibitor, LY294002 and the p38 MAPK inhibitor SB203580 had synergistic effects on cell viability in all three cell lines. Conclusions c-MYC- and PI3K/mTOR-inhibitors decreased viability of the lymphoma cells and led to decreased glucose uptake, expression of glycolysis-associated genes, and glucose metabolism-regulating miRNAs. Inhibition of HK by 2-DG reduced cell numbers as a single agent and synergistically with inhibitors of other intracellular pathways. Thus, targeted inhibition of the pathways investigated here could be a strategy to suppress the glycolytic phenotype of lymphoma cells and reduce proliferation. |
| first_indexed | 2024-12-19T18:14:47Z |
| format | Article |
| id | doaj.art-d6a866641f184e439a25b9977f6204db |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-19T18:14:47Z |
| publishDate | 2017-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-d6a866641f184e439a25b9977f6204db2022-12-21T20:11:09ZengBMCJournal of Translational Medicine1479-58762017-07-0115111510.1186/s12967-017-1258-9Regulation of glucose uptake in lymphoma cell lines by c-MYC- and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viabilityMartina Broecker-Preuss0Nina Becher-Boveleth1Andreas Bockisch2Ulrich Dührsen3Stefan Müller4Department of Nuclear Medicine, University Hospital EssenDepartment of Nuclear Medicine, University Hospital EssenDepartment of Nuclear Medicine, University Hospital EssenDepartment of Hematology, University Hospital EssenDepartment of Nuclear Medicine, University Hospital EssenAbstract Background Changes in glucose and energy metabolism contribute to the altered phenotype of cancer cells and are the basis for positron emission tomography with 18F-fluoro-2-deoxy-d-glucose (FDG) to visualize tumors in vivo. The molecular background of the enhanced glucose uptake and its regulation in lymphoma cells is not fully clarified and may provide new possibilities to reverse the altered metabolism. Thus in this study we investigated regulation of glucose uptake by different signaling pathways. Furthermore, the effect of the glucose analog 2-deoxy-d-glucose (2-DG) alone and in combination with other inhibitors on cell survival was studied. Methods An FDG uptake assay was established and uptake of FDG by lymphoma cells was determined after incubation with inhibitors of the c-MYC and the PI3K signalling pathways that are known to be activated in lymphoma cells and able to regulate glucose metabolism. Inhibitors of MAPK signalling pathways whose role in altered metabolism is still unclear were also investigated. Expression of mRNAs of the glucose transporter 1 (GLUT1), hexokinase 2 (HK2), glucose-6-phosphatase (G6Pase) and lactate dehydrogenase A (LDHA) and of the glucose metabolism-regulating micro RNAs (miRNA) miR21, -23a, -133a, -133b, -138-1 and -143 was determined by RT-PCR. Cell viability was analysed by MTT assay. Results Treatment with the c-MYC inhibitor 10058-F4 and inhibitors of the PI3K/mTOR pathway diminished uptake of FDG in all three cell lines, while inhibition of MAPK pathways had no effect on glucose uptake. Expression of glycolysis-related genes and miRNAs were diminished, although to a variable degree in the three cell lines. The c-MYC inhibitor, the PI3K inhibitor LY294002, the mTOR inhibitor Rapamycin and 2-DG all diminished the number of viable cells. Interestingly, in combination with 2-DG, the c-MYC inhibitor, LY294002 and the p38 MAPK inhibitor SB203580 had synergistic effects on cell viability in all three cell lines. Conclusions c-MYC- and PI3K/mTOR-inhibitors decreased viability of the lymphoma cells and led to decreased glucose uptake, expression of glycolysis-associated genes, and glucose metabolism-regulating miRNAs. Inhibition of HK by 2-DG reduced cell numbers as a single agent and synergistically with inhibitors of other intracellular pathways. Thus, targeted inhibition of the pathways investigated here could be a strategy to suppress the glycolytic phenotype of lymphoma cells and reduce proliferation.http://link.springer.com/article/10.1186/s12967-017-1258-9Warburg effectGlucose metabolismLymphoma18F-fluoro-2-deoxy-d-glucose2-deoxy-d-glucose |
| spellingShingle | Martina Broecker-Preuss Nina Becher-Boveleth Andreas Bockisch Ulrich Dührsen Stefan Müller Regulation of glucose uptake in lymphoma cell lines by c-MYC- and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viability Journal of Translational Medicine Warburg effect Glucose metabolism Lymphoma 18F-fluoro-2-deoxy-d-glucose 2-deoxy-d-glucose |
| title | Regulation of glucose uptake in lymphoma cell lines by c-MYC- and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viability |
| title_full | Regulation of glucose uptake in lymphoma cell lines by c-MYC- and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viability |
| title_fullStr | Regulation of glucose uptake in lymphoma cell lines by c-MYC- and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viability |
| title_full_unstemmed | Regulation of glucose uptake in lymphoma cell lines by c-MYC- and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viability |
| title_short | Regulation of glucose uptake in lymphoma cell lines by c-MYC- and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viability |
| title_sort | regulation of glucose uptake in lymphoma cell lines by c myc and pi3k dependent signaling pathways and impact of glycolytic pathways on cell viability |
| topic | Warburg effect Glucose metabolism Lymphoma 18F-fluoro-2-deoxy-d-glucose 2-deoxy-d-glucose |
| url | http://link.springer.com/article/10.1186/s12967-017-1258-9 |
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