Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death
Abstract The altered metabolism of cancer can render cells dependent on the availability of metabolic substrates for viability. Investigating the signaling mechanisms underlying cell death in cells dependent upon glucose for survival, we demonstrate that glucose withdrawal rapidly induces supra‐phys...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2012-06-01
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| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/msb.2012.20 |
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| _version_ | 1849389471892504576 |
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| author | Nicholas A Graham Martik Tahmasian Bitika Kohli Evangelia Komisopoulou Maggie Zhu Igor Vivanco Michael A Teitell Hong Wu Antoni Ribas Roger S Lo Ingo K Mellinghoff Paul S Mischel Thomas G Graeber |
| author_facet | Nicholas A Graham Martik Tahmasian Bitika Kohli Evangelia Komisopoulou Maggie Zhu Igor Vivanco Michael A Teitell Hong Wu Antoni Ribas Roger S Lo Ingo K Mellinghoff Paul S Mischel Thomas G Graeber |
| author_sort | Nicholas A Graham |
| collection | DOAJ |
| description | Abstract The altered metabolism of cancer can render cells dependent on the availability of metabolic substrates for viability. Investigating the signaling mechanisms underlying cell death in cells dependent upon glucose for survival, we demonstrate that glucose withdrawal rapidly induces supra‐physiological levels of phospho‐tyrosine signaling, even in cells expressing constitutively active tyrosine kinases. Using unbiased mass spectrometry‐based phospho‐proteomics, we show that glucose withdrawal initiates a unique signature of phospho‐tyrosine activation that is associated with focal adhesions. Building upon this observation, we demonstrate that glucose withdrawal activates a positive feedback loop involving generation of reactive oxygen species (ROS) by NADPH oxidase and mitochondria, inhibition of protein tyrosine phosphatases by oxidation, and increased tyrosine kinase signaling. In cells dependent on glucose for survival, glucose withdrawal‐induced ROS generation and tyrosine kinase signaling synergize to amplify ROS levels, ultimately resulting in ROS‐mediated cell death. Taken together, these findings illustrate the systems‐level cross‐talk between metabolism and signaling in the maintenance of cancer cell homeostasis. |
| format | Article |
| id | doaj-art-ee846cbd9aaa4f49a9bd39d8351540f9 |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2012-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-ee846cbd9aaa4f49a9bd39d8351540f92025-08-20T03:41:57ZengSpringer NatureMolecular Systems Biology1744-42922012-06-018111610.1038/msb.2012.20Glucose deprivation activates a metabolic and signaling amplification loop leading to cell deathNicholas A Graham0Martik Tahmasian1Bitika Kohli2Evangelia Komisopoulou3Maggie Zhu4Igor Vivanco5Michael A Teitell6Hong Wu7Antoni Ribas8Roger S Lo9Ingo K Mellinghoff10Paul S Mischel11Thomas G Graeber12Crump Institute for Molecular Imaging, University of CaliforniaCrump Institute for Molecular Imaging, University of CaliforniaCrump Institute for Molecular Imaging, University of CaliforniaCrump Institute for Molecular Imaging, University of CaliforniaCrump Institute for Molecular Imaging, University of CaliforniaHuman Oncology and Pathogenesis Program, Memorial Sloan‐Kettering Cancer CenterDepartment of Pathology and Laboratory Medicine, University of CaliforniaDepartment of Molecular and Medical Pharmacology, University of CaliforniaDepartment of Molecular and Medical Pharmacology, University of CaliforniaDepartment of Molecular and Medical Pharmacology, University of CaliforniaHuman Oncology and Pathogenesis Program, Memorial Sloan‐Kettering Cancer CenterDepartment of Molecular and Medical Pharmacology, University of CaliforniaCrump Institute for Molecular Imaging, University of CaliforniaAbstract The altered metabolism of cancer can render cells dependent on the availability of metabolic substrates for viability. Investigating the signaling mechanisms underlying cell death in cells dependent upon glucose for survival, we demonstrate that glucose withdrawal rapidly induces supra‐physiological levels of phospho‐tyrosine signaling, even in cells expressing constitutively active tyrosine kinases. Using unbiased mass spectrometry‐based phospho‐proteomics, we show that glucose withdrawal initiates a unique signature of phospho‐tyrosine activation that is associated with focal adhesions. Building upon this observation, we demonstrate that glucose withdrawal activates a positive feedback loop involving generation of reactive oxygen species (ROS) by NADPH oxidase and mitochondria, inhibition of protein tyrosine phosphatases by oxidation, and increased tyrosine kinase signaling. In cells dependent on glucose for survival, glucose withdrawal‐induced ROS generation and tyrosine kinase signaling synergize to amplify ROS levels, ultimately resulting in ROS‐mediated cell death. Taken together, these findings illustrate the systems‐level cross‐talk between metabolism and signaling in the maintenance of cancer cell homeostasis.https://doi.org/10.1038/msb.2012.20cancermetabolismphosphataseproteomicsreactive oxygen species |
| spellingShingle | Nicholas A Graham Martik Tahmasian Bitika Kohli Evangelia Komisopoulou Maggie Zhu Igor Vivanco Michael A Teitell Hong Wu Antoni Ribas Roger S Lo Ingo K Mellinghoff Paul S Mischel Thomas G Graeber Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death Molecular Systems Biology cancer metabolism phosphatase proteomics reactive oxygen species |
| title | Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death |
| title_full | Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death |
| title_fullStr | Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death |
| title_full_unstemmed | Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death |
| title_short | Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death |
| title_sort | glucose deprivation activates a metabolic and signaling amplification loop leading to cell death |
| topic | cancer metabolism phosphatase proteomics reactive oxygen species |
| url | https://doi.org/10.1038/msb.2012.20 |
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