In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation
Hypoxic and VHL-deficient cells use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate. To gain insights into the role of HIF and the molecular mechanisms underlying RC, we took advantage of a panel of disease-associated VHL mutants and showed that HIF e...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/101235 https://orcid.org/0000-0001-6909-4568 |
| _version_ | 1826192091682701312 |
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| author | Gameiro, Paulo A. Yang, Juanjuan Metelo, Ana M. Baker, Rania Wang, Zongwei Arreola, Alexandra Rathmell, W. Kimryn Olumi, Aria F. Stephanopoulos, Gregory Iliopoulos, Othon Perez-Carro, Rocio Lopez-Larrubia, Pilar Gameiro, Paulo A. |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering Gameiro, Paulo A. Yang, Juanjuan Metelo, Ana M. Baker, Rania Wang, Zongwei Arreola, Alexandra Rathmell, W. Kimryn Olumi, Aria F. Stephanopoulos, Gregory Iliopoulos, Othon Perez-Carro, Rocio Lopez-Larrubia, Pilar Gameiro, Paulo A. |
| author_sort | Gameiro, Paulo A. |
| collection | MIT |
| description | Hypoxic and VHL-deficient cells use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate. To gain insights into the role of HIF and the molecular mechanisms underlying RC, we took advantage of a panel of disease-associated VHL mutants and showed that HIF expression is necessary and sufficient for the induction of RC in human renal cell carcinoma (RCC) cells. HIF expression drastically reduced intracellular citrate levels. Feeding VHL-deficient RCC cells with acetate or citrate or knocking down PDK-1 and ACLY restored citrate levels and suppressed RC. These data suggest that HIF-induced low intracellular citrate levels promote the reductive flux by mass action to maintain lipogenesis. Using [[superscript 1–13]C]glutamine, we demonstrated in vivo RC activity in VHL-deficient tumors growing as xenografts in mice. Lastly, HIF rendered VHL-deficient cells sensitive to glutamine deprivation in vitro, and systemic administration of glutaminase inhibitors suppressed the growth of RCC cells as mice xenografts. |
| first_indexed | 2024-09-23T09:06:08Z |
| format | Article |
| id | mit-1721.1/101235 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:06:08Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1012352022-09-26T10:28:27Z In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation Gameiro, Paulo A. Yang, Juanjuan Metelo, Ana M. Baker, Rania Wang, Zongwei Arreola, Alexandra Rathmell, W. Kimryn Olumi, Aria F. Stephanopoulos, Gregory Iliopoulos, Othon Perez-Carro, Rocio Lopez-Larrubia, Pilar Gameiro, Paulo A. Massachusetts Institute of Technology. Department of Chemical Engineering Gameiro, Paulo A. Stephanopoulos, Gregory Hypoxic and VHL-deficient cells use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate. To gain insights into the role of HIF and the molecular mechanisms underlying RC, we took advantage of a panel of disease-associated VHL mutants and showed that HIF expression is necessary and sufficient for the induction of RC in human renal cell carcinoma (RCC) cells. HIF expression drastically reduced intracellular citrate levels. Feeding VHL-deficient RCC cells with acetate or citrate or knocking down PDK-1 and ACLY restored citrate levels and suppressed RC. These data suggest that HIF-induced low intracellular citrate levels promote the reductive flux by mass action to maintain lipogenesis. Using [[superscript 1–13]C]glutamine, we demonstrated in vivo RC activity in VHL-deficient tumors growing as xenografts in mice. Lastly, HIF rendered VHL-deficient cells sensitive to glutamine deprivation in vitro, and systemic administration of glutaminase inhibitors suppressed the growth of RCC cells as mice xenografts. Fundacao para a Ciencia e a Tecnologia National Institutes of Health (U.S.) (R01 DK075850) 2016-02-23T00:34:12Z 2016-02-23T00:34:12Z 2013-03 2012-09 Article http://purl.org/eprint/type/JournalArticle 15504131 1932-7420 http://hdl.handle.net/1721.1/101235 Gameiro, Paulo A., Juanjuan Yang, Ana M. Metelo, Rocio Parez-Carro, Rania Baker, Zongwei Wang, Alexandra Arreola, et al. “In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation.” Cell Metabolism 17, no. 3 (March 2013): 372–385. https://orcid.org/0000-0001-6909-4568 en_US http://dx.doi.org/10.1016/j.cmet.2013.02.002 Cell Metabolism Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Gameiro, Paulo A. Yang, Juanjuan Metelo, Ana M. Baker, Rania Wang, Zongwei Arreola, Alexandra Rathmell, W. Kimryn Olumi, Aria F. Stephanopoulos, Gregory Iliopoulos, Othon Perez-Carro, Rocio Lopez-Larrubia, Pilar Gameiro, Paulo A. In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation |
| title | In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation |
| title_full | In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation |
| title_fullStr | In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation |
| title_full_unstemmed | In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation |
| title_short | In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation |
| title_sort | in vivo hif mediated reductive carboxylation is regulated by citrate levels and sensitizes vhl deficient cells to glutamine deprivation |
| url | http://hdl.handle.net/1721.1/101235 https://orcid.org/0000-0001-6909-4568 |
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