Activation of AKT via a dual mechanism enhances the susceptibility of melanoma cells to glucose deprivation
Abstract Protein kinase AKT plays a broad role in promoting energy production in nutrient-rich environments. However, its roles under metabolic stress remain elusive. Herein, we demonstrate a dual mechanism for AKT activation during glucose deprivation. On one hand, glucose deprivation leads to incr...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07906-4 |
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| author | Guang-xi Yang De-liang Peng Lin Chen Yu Qian Le He Xiao-yan Chen Wen-bin Hong Cai-ming Wu Hang-zi Chen |
| author_facet | Guang-xi Yang De-liang Peng Lin Chen Yu Qian Le He Xiao-yan Chen Wen-bin Hong Cai-ming Wu Hang-zi Chen |
| author_sort | Guang-xi Yang |
| collection | DOAJ |
| description | Abstract Protein kinase AKT plays a broad role in promoting energy production in nutrient-rich environments. However, its roles under metabolic stress remain elusive. Herein, we demonstrate a dual mechanism for AKT activation during glucose deprivation. On one hand, glucose deprivation leads to increased levels of ADP and NADP+, which directly bind to spleen tyrosine kinase (SYK) and induce a conformational alteration of SYK, resulting in self-activation. The activated SYK further triggers PI3K-dependent activation of AKT. On the other hand, elevated ROS upon glucose deprivation promotes oxidative dimerization of PDK1, thereby facilitating the recognition and activation of AKT. In melanoma cells, AKT plays a critical role in elevating ROS levels and inducing cell death during glucose deprivation. Overall, this study not only establishes a novel connection between energy insufficiency and AKT activation via a dual mechanism but also provides insights into the role of AKT in sensitizing cells to metabolic stress. |
| format | Article |
| id | doaj-art-ed19950e4cf04014a5ddf90f8ab2c085 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-ed19950e4cf04014a5ddf90f8ab2c0852025-08-20T03:06:09ZengNature Publishing GroupCell Death and Disease2041-48892025-08-0116111510.1038/s41419-025-07906-4Activation of AKT via a dual mechanism enhances the susceptibility of melanoma cells to glucose deprivationGuang-xi Yang0De-liang Peng1Lin Chen2Yu Qian3Le He4Xiao-yan Chen5Wen-bin Hong6Cai-ming Wu7Hang-zi Chen8The First Affiliated Hospital of Xiamen University, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen UniversityThe First Affiliated Hospital of Xiamen University, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen UniversityThe First Affiliated Hospital of Xiamen University, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen UniversityThe First Affiliated Hospital of Xiamen University, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen UniversityThe First Affiliated Hospital of Xiamen University, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen UniversityThe First Affiliated Hospital of Xiamen University, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen UniversityThe First Affiliated Hospital of Xiamen University, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen UniversityThe First Affiliated Hospital of Xiamen University, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen UniversityThe First Affiliated Hospital of Xiamen University, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen UniversityAbstract Protein kinase AKT plays a broad role in promoting energy production in nutrient-rich environments. However, its roles under metabolic stress remain elusive. Herein, we demonstrate a dual mechanism for AKT activation during glucose deprivation. On one hand, glucose deprivation leads to increased levels of ADP and NADP+, which directly bind to spleen tyrosine kinase (SYK) and induce a conformational alteration of SYK, resulting in self-activation. The activated SYK further triggers PI3K-dependent activation of AKT. On the other hand, elevated ROS upon glucose deprivation promotes oxidative dimerization of PDK1, thereby facilitating the recognition and activation of AKT. In melanoma cells, AKT plays a critical role in elevating ROS levels and inducing cell death during glucose deprivation. Overall, this study not only establishes a novel connection between energy insufficiency and AKT activation via a dual mechanism but also provides insights into the role of AKT in sensitizing cells to metabolic stress.https://doi.org/10.1038/s41419-025-07906-4 |
| spellingShingle | Guang-xi Yang De-liang Peng Lin Chen Yu Qian Le He Xiao-yan Chen Wen-bin Hong Cai-ming Wu Hang-zi Chen Activation of AKT via a dual mechanism enhances the susceptibility of melanoma cells to glucose deprivation Cell Death and Disease |
| title | Activation of AKT via a dual mechanism enhances the susceptibility of melanoma cells to glucose deprivation |
| title_full | Activation of AKT via a dual mechanism enhances the susceptibility of melanoma cells to glucose deprivation |
| title_fullStr | Activation of AKT via a dual mechanism enhances the susceptibility of melanoma cells to glucose deprivation |
| title_full_unstemmed | Activation of AKT via a dual mechanism enhances the susceptibility of melanoma cells to glucose deprivation |
| title_short | Activation of AKT via a dual mechanism enhances the susceptibility of melanoma cells to glucose deprivation |
| title_sort | activation of akt via a dual mechanism enhances the susceptibility of melanoma cells to glucose deprivation |
| url | https://doi.org/10.1038/s41419-025-07906-4 |
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