Disruption of β-catenin-mediated negative feedback reinforces cAMP-induced neuronal differentiation in glioma stem cells
Abstract Accumulating evidence supports the existence of glioma stem cells (GSCs) and their critical role in the resistance to conventional treatments for glioblastoma multiforme (GBM). Differentiation therapy represents a promising alternative strategy against GBM by forcing GSCs to exit the cell c...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-05-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04957-9 |
| _version_ | 1828796399914844160 |
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| author | Zhijie Chen Yingqian Zhong Jiehong Chen Shuxin Sun Wenfeng Liu Yu Han Xincheng Liu Cui Guo Depei Li Wanming Hu Peiyu Zhang Zhuopeng Chen Zhongping Chen Yonggao Mou Guangmei Yan Wenbo Zhu Wei Yin Ke Sai |
| author_facet | Zhijie Chen Yingqian Zhong Jiehong Chen Shuxin Sun Wenfeng Liu Yu Han Xincheng Liu Cui Guo Depei Li Wanming Hu Peiyu Zhang Zhuopeng Chen Zhongping Chen Yonggao Mou Guangmei Yan Wenbo Zhu Wei Yin Ke Sai |
| author_sort | Zhijie Chen |
| collection | DOAJ |
| description | Abstract Accumulating evidence supports the existence of glioma stem cells (GSCs) and their critical role in the resistance to conventional treatments for glioblastoma multiforme (GBM). Differentiation therapy represents a promising alternative strategy against GBM by forcing GSCs to exit the cell cycle and reach terminal differentiation. In this study, we demonstrated that cAMP triggered neuronal differentiation and compromised the self-renewal capacity in GSCs. In addition, cAMP induced negative feedback to antagonize the differentiation process by activating β-catenin pathway. Suppression of β-catenin signaling synergized with cAMP activators to eliminate GSCs in vitro and extended the survival of animals in vivo. The cAMP/PKA pathway stabilized β-catenin through direct phosphorylation of the molecule and inhibition of GSK-3β. The activated β-catenin translocated into the nucleus and promoted the transcription of APELA and CARD16, which were found to be responsible for the repression of cAMP-induced differentiation in GSCs. Overall, our findings identified a negative feedback mechanism for cAMP-induced differentiation in GSCs and provided potential targets for the reinforcement of differentiation therapy for GBM. |
| first_indexed | 2024-12-12T04:22:13Z |
| format | Article |
| id | doaj.art-291e123fdb414f51bac2c92ab67ce0eb |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-12T04:22:13Z |
| publishDate | 2022-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-291e123fdb414f51bac2c92ab67ce0eb2022-12-22T00:38:17ZengNature Publishing GroupCell Death and Disease2041-48892022-05-0113511310.1038/s41419-022-04957-9Disruption of β-catenin-mediated negative feedback reinforces cAMP-induced neuronal differentiation in glioma stem cellsZhijie Chen0Yingqian Zhong1Jiehong Chen2Shuxin Sun3Wenfeng Liu4Yu Han5Xincheng Liu6Cui Guo7Depei Li8Wanming Hu9Peiyu Zhang10Zhuopeng Chen11Zhongping Chen12Yonggao Mou13Guangmei Yan14Wenbo Zhu15Wei Yin16Ke Sai17Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer CenterDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Pancreas Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical SciencesDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer CenterDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer CenterDepartment of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer CenterDepartment of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer CenterDepartment of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer CenterDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen UniversityDepartment of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer CenterAbstract Accumulating evidence supports the existence of glioma stem cells (GSCs) and their critical role in the resistance to conventional treatments for glioblastoma multiforme (GBM). Differentiation therapy represents a promising alternative strategy against GBM by forcing GSCs to exit the cell cycle and reach terminal differentiation. In this study, we demonstrated that cAMP triggered neuronal differentiation and compromised the self-renewal capacity in GSCs. In addition, cAMP induced negative feedback to antagonize the differentiation process by activating β-catenin pathway. Suppression of β-catenin signaling synergized with cAMP activators to eliminate GSCs in vitro and extended the survival of animals in vivo. The cAMP/PKA pathway stabilized β-catenin through direct phosphorylation of the molecule and inhibition of GSK-3β. The activated β-catenin translocated into the nucleus and promoted the transcription of APELA and CARD16, which were found to be responsible for the repression of cAMP-induced differentiation in GSCs. Overall, our findings identified a negative feedback mechanism for cAMP-induced differentiation in GSCs and provided potential targets for the reinforcement of differentiation therapy for GBM.https://doi.org/10.1038/s41419-022-04957-9 |
| spellingShingle | Zhijie Chen Yingqian Zhong Jiehong Chen Shuxin Sun Wenfeng Liu Yu Han Xincheng Liu Cui Guo Depei Li Wanming Hu Peiyu Zhang Zhuopeng Chen Zhongping Chen Yonggao Mou Guangmei Yan Wenbo Zhu Wei Yin Ke Sai Disruption of β-catenin-mediated negative feedback reinforces cAMP-induced neuronal differentiation in glioma stem cells Cell Death and Disease |
| title | Disruption of β-catenin-mediated negative feedback reinforces cAMP-induced neuronal differentiation in glioma stem cells |
| title_full | Disruption of β-catenin-mediated negative feedback reinforces cAMP-induced neuronal differentiation in glioma stem cells |
| title_fullStr | Disruption of β-catenin-mediated negative feedback reinforces cAMP-induced neuronal differentiation in glioma stem cells |
| title_full_unstemmed | Disruption of β-catenin-mediated negative feedback reinforces cAMP-induced neuronal differentiation in glioma stem cells |
| title_short | Disruption of β-catenin-mediated negative feedback reinforces cAMP-induced neuronal differentiation in glioma stem cells |
| title_sort | disruption of β catenin mediated negative feedback reinforces camp induced neuronal differentiation in glioma stem cells |
| url | https://doi.org/10.1038/s41419-022-04957-9 |
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