A positive feedback loop between Myc and aerobic glycolysis sustains tumor growth in a Drosophila tumor model
Cancer cells usually exhibit aberrant cell signaling and metabolic reprogramming. However, mechanisms of crosstalk between these processes remain elusive. Here, we show that in an in vivo tumor model expressing oncogenic Drosophila Homeodomain-interacting protein kinase (Hipk), tumor cells display e...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-07-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/46315 |
| _version_ | 1811253256475639808 |
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| author | Kenneth Kin Lam Wong Jenny Zhe Liao Esther M Verheyen |
| author_facet | Kenneth Kin Lam Wong Jenny Zhe Liao Esther M Verheyen |
| author_sort | Kenneth Kin Lam Wong |
| collection | DOAJ |
| description | Cancer cells usually exhibit aberrant cell signaling and metabolic reprogramming. However, mechanisms of crosstalk between these processes remain elusive. Here, we show that in an in vivo tumor model expressing oncogenic Drosophila Homeodomain-interacting protein kinase (Hipk), tumor cells display elevated aerobic glycolysis. Mechanistically, elevated Hipk drives transcriptional upregulation of Drosophila Myc (dMyc; MYC in vertebrates) likely through convergence of multiple perturbed signaling cascades. dMyc induces robust expression of pfk2 (encoding 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase; PFKFB in vertebrates) among other glycolytic genes. Pfk2 catalyzes the synthesis of fructose-2,6-bisphosphate, which acts as a potent allosteric activator of Phosphofructokinase (Pfk) and thus stimulates glycolysis. Pfk2 and Pfk in turn are required to sustain dMyc protein accumulation post-transcriptionally, establishing a positive feedback loop. Disruption of the loop abrogates tumorous growth. Together, our study demonstrates a reciprocal stimulation of Myc and aerobic glycolysis and identifies the Pfk2-Pfk governed committed step of glycolysis as a metabolic vulnerability during tumorigenesis. |
| first_indexed | 2024-04-12T16:48:13Z |
| format | Article |
| id | doaj.art-8aad676db13d443c83a547bbce43d4b8 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:48:13Z |
| publishDate | 2019-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8aad676db13d443c83a547bbce43d4b82022-12-22T03:24:31ZengeLife Sciences Publications LtdeLife2050-084X2019-07-01810.7554/eLife.46315A positive feedback loop between Myc and aerobic glycolysis sustains tumor growth in a Drosophila tumor modelKenneth Kin Lam Wong0Jenny Zhe Liao1Esther M Verheyen2https://orcid.org/0000-0002-9795-5094Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; Centre for Cell Biology Development and Disease, Simon Fraser University, Burnaby, CanadaDepartment of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, CanadaDepartment of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada; Centre for Cell Biology Development and Disease, Simon Fraser University, Burnaby, CanadaCancer cells usually exhibit aberrant cell signaling and metabolic reprogramming. However, mechanisms of crosstalk between these processes remain elusive. Here, we show that in an in vivo tumor model expressing oncogenic Drosophila Homeodomain-interacting protein kinase (Hipk), tumor cells display elevated aerobic glycolysis. Mechanistically, elevated Hipk drives transcriptional upregulation of Drosophila Myc (dMyc; MYC in vertebrates) likely through convergence of multiple perturbed signaling cascades. dMyc induces robust expression of pfk2 (encoding 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase; PFKFB in vertebrates) among other glycolytic genes. Pfk2 catalyzes the synthesis of fructose-2,6-bisphosphate, which acts as a potent allosteric activator of Phosphofructokinase (Pfk) and thus stimulates glycolysis. Pfk2 and Pfk in turn are required to sustain dMyc protein accumulation post-transcriptionally, establishing a positive feedback loop. Disruption of the loop abrogates tumorous growth. Together, our study demonstrates a reciprocal stimulation of Myc and aerobic glycolysis and identifies the Pfk2-Pfk governed committed step of glycolysis as a metabolic vulnerability during tumorigenesis.https://elifesciences.org/articles/46315Drosophila cancer modelphosphofructokinaseaerobic glycolysisMYCphosphofructokinase 2Hipk |
| spellingShingle | Kenneth Kin Lam Wong Jenny Zhe Liao Esther M Verheyen A positive feedback loop between Myc and aerobic glycolysis sustains tumor growth in a Drosophila tumor model eLife Drosophila cancer model phosphofructokinase aerobic glycolysis MYC phosphofructokinase 2 Hipk |
| title | A positive feedback loop between Myc and aerobic glycolysis sustains tumor growth in a Drosophila tumor model |
| title_full | A positive feedback loop between Myc and aerobic glycolysis sustains tumor growth in a Drosophila tumor model |
| title_fullStr | A positive feedback loop between Myc and aerobic glycolysis sustains tumor growth in a Drosophila tumor model |
| title_full_unstemmed | A positive feedback loop between Myc and aerobic glycolysis sustains tumor growth in a Drosophila tumor model |
| title_short | A positive feedback loop between Myc and aerobic glycolysis sustains tumor growth in a Drosophila tumor model |
| title_sort | positive feedback loop between myc and aerobic glycolysis sustains tumor growth in a drosophila tumor model |
| topic | Drosophila cancer model phosphofructokinase aerobic glycolysis MYC phosphofructokinase 2 Hipk |
| url | https://elifesciences.org/articles/46315 |
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