Genetic Disruption of the γ-Glutamylcysteine Ligase in PDAC Cells Induces Ferroptosis-Independent Cell Death In Vitro without Affecting In Vivo Tumor Growth
The conceptualization of a novel type of cell death, called ferroptosis, opens new avenues for the development of more efficient anti-cancer therapeutics. In this context, a full understanding of the ferroptotic pathways, the players involved, their precise role, and dispensability is prerequisite....
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| Format: | Article |
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MDPI AG
2022-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/13/3154 |
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| author | Boutaina Daher Willian Meira Jerome Durivault Celia Gotorbe Jacques Pouyssegur Milica Vucetic |
| author_facet | Boutaina Daher Willian Meira Jerome Durivault Celia Gotorbe Jacques Pouyssegur Milica Vucetic |
| author_sort | Boutaina Daher |
| collection | DOAJ |
| description | The conceptualization of a novel type of cell death, called ferroptosis, opens new avenues for the development of more efficient anti-cancer therapeutics. In this context, a full understanding of the ferroptotic pathways, the players involved, their precise role, and dispensability is prerequisite. Here, we focused on the importance of glutathione (GSH) for ferroptosis prevention in pancreatic ductal adenocarcinoma (PDAC) cells. We genetically deleted a unique, rate-limiting enzyme for GSH biosynthesis, γ-glutamylcysteine ligase (GCL), which plays a key role in tumor cell proliferation and survival. Surprisingly, although glutathione peroxidase 4 (GPx4) has been described as a guardian of ferroptosis, depletion of its substrate (GSH) led preferentially to apoptotic cell death, while classical ferroptotic markers (lipid hydroperoxides) have not been observed. Furthermore, the sensitivity of PDAC cells to the pharmacological/genetic inhibition of GPx4 revealed GSH dispensability in this context. To the best of our knowledge, this is the first time that the complete dissection of the xCT-GSH-GPx4 axis in PDAC cells has been investigated in great detail. Collectively, our results revealed the necessary role of GSH in the overall redox homeostasis of PDAC cells, as well as the dispensability of this redox-active molecule for a specific, antioxidant branch dedicated to ferroptosis prevention. |
| first_indexed | 2024-03-09T22:03:55Z |
| format | Article |
| id | doaj.art-ca28146d5ae94a2d930b514711a89a92 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T22:03:55Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ca28146d5ae94a2d930b514711a89a922023-11-23T19:45:20ZengMDPI AGCancers2072-66942022-06-011413315410.3390/cancers14133154Genetic Disruption of the γ-Glutamylcysteine Ligase in PDAC Cells Induces Ferroptosis-Independent Cell Death In Vitro without Affecting In Vivo Tumor GrowthBoutaina Daher0Willian Meira1Jerome Durivault2Celia Gotorbe3Jacques Pouyssegur4Milica Vucetic5Medical Biology Department, Centre Scientifique de Monaco (CSM), 98000 Monaco, MonacoMedical Biology Department, Centre Scientifique de Monaco (CSM), 98000 Monaco, MonacoMedical Biology Department, Centre Scientifique de Monaco (CSM), 98000 Monaco, MonacoMedical Biology Department, Centre Scientifique de Monaco (CSM), 98000 Monaco, MonacoMedical Biology Department, Centre Scientifique de Monaco (CSM), 98000 Monaco, MonacoMedical Biology Department, Centre Scientifique de Monaco (CSM), 98000 Monaco, MonacoThe conceptualization of a novel type of cell death, called ferroptosis, opens new avenues for the development of more efficient anti-cancer therapeutics. In this context, a full understanding of the ferroptotic pathways, the players involved, their precise role, and dispensability is prerequisite. Here, we focused on the importance of glutathione (GSH) for ferroptosis prevention in pancreatic ductal adenocarcinoma (PDAC) cells. We genetically deleted a unique, rate-limiting enzyme for GSH biosynthesis, γ-glutamylcysteine ligase (GCL), which plays a key role in tumor cell proliferation and survival. Surprisingly, although glutathione peroxidase 4 (GPx4) has been described as a guardian of ferroptosis, depletion of its substrate (GSH) led preferentially to apoptotic cell death, while classical ferroptotic markers (lipid hydroperoxides) have not been observed. Furthermore, the sensitivity of PDAC cells to the pharmacological/genetic inhibition of GPx4 revealed GSH dispensability in this context. To the best of our knowledge, this is the first time that the complete dissection of the xCT-GSH-GPx4 axis in PDAC cells has been investigated in great detail. Collectively, our results revealed the necessary role of GSH in the overall redox homeostasis of PDAC cells, as well as the dispensability of this redox-active molecule for a specific, antioxidant branch dedicated to ferroptosis prevention.https://www.mdpi.com/2072-6694/14/13/3154ferroptosisglutathineγ-glutamylcysteine ligaseGPx4lipid hydroperoxides |
| spellingShingle | Boutaina Daher Willian Meira Jerome Durivault Celia Gotorbe Jacques Pouyssegur Milica Vucetic Genetic Disruption of the γ-Glutamylcysteine Ligase in PDAC Cells Induces Ferroptosis-Independent Cell Death In Vitro without Affecting In Vivo Tumor Growth Cancers ferroptosis glutathine γ-glutamylcysteine ligase GPx4 lipid hydroperoxides |
| title | Genetic Disruption of the γ-Glutamylcysteine Ligase in PDAC Cells Induces Ferroptosis-Independent Cell Death In Vitro without Affecting In Vivo Tumor Growth |
| title_full | Genetic Disruption of the γ-Glutamylcysteine Ligase in PDAC Cells Induces Ferroptosis-Independent Cell Death In Vitro without Affecting In Vivo Tumor Growth |
| title_fullStr | Genetic Disruption of the γ-Glutamylcysteine Ligase in PDAC Cells Induces Ferroptosis-Independent Cell Death In Vitro without Affecting In Vivo Tumor Growth |
| title_full_unstemmed | Genetic Disruption of the γ-Glutamylcysteine Ligase in PDAC Cells Induces Ferroptosis-Independent Cell Death In Vitro without Affecting In Vivo Tumor Growth |
| title_short | Genetic Disruption of the γ-Glutamylcysteine Ligase in PDAC Cells Induces Ferroptosis-Independent Cell Death In Vitro without Affecting In Vivo Tumor Growth |
| title_sort | genetic disruption of the γ glutamylcysteine ligase in pdac cells induces ferroptosis independent cell death in vitro without affecting in vivo tumor growth |
| topic | ferroptosis glutathine γ-glutamylcysteine ligase GPx4 lipid hydroperoxides |
| url | https://www.mdpi.com/2072-6694/14/13/3154 |
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