GNE‐317 Reverses MSN‐Mediated Proneural‐to‐Mesenchymal Transition and Suppresses Chemoradiotherapy Resistance in Glioblastoma via PI3K/mTOR
Abstract Glioblastoma (GBM) resistance to chemoradiotherapy is a major factor contributing to poor treatment outcomes. This resistance markedly affects the effectiveness of surgery combined with chemoradiotherapy and leads to post‐surgical tumor recurrence. Therefore, exploring the mechanisms underl...
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| Format: | Article |
| Language: | English |
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Wiley
2025-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202412517 |
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| author | Yong‐Chang Yang Xing‐Yu Jin Ling‐Ling Yang Xing Xu Yang Xie Yi‐Ding Ai Xin‐Chao Li Ye‐Cheng Ma Cheng‐Long Xu Qi Li Xiang‐Lian Ge Tai‐Long Yi Tao Jiang Xiao‐Guang Wang Ying‐Zhe Piao Xun Jin |
| author_facet | Yong‐Chang Yang Xing‐Yu Jin Ling‐Ling Yang Xing Xu Yang Xie Yi‐Ding Ai Xin‐Chao Li Ye‐Cheng Ma Cheng‐Long Xu Qi Li Xiang‐Lian Ge Tai‐Long Yi Tao Jiang Xiao‐Guang Wang Ying‐Zhe Piao Xun Jin |
| author_sort | Yong‐Chang Yang |
| collection | DOAJ |
| description | Abstract Glioblastoma (GBM) resistance to chemoradiotherapy is a major factor contributing to poor treatment outcomes. This resistance markedly affects the effectiveness of surgery combined with chemoradiotherapy and leads to post‐surgical tumor recurrence. Therefore, exploring the mechanisms underlying chemoradiotherapy resistance in GBM is crucial for understanding its progression and improving therapeutic options. This study found that moesin (MSN) acts as a key promotor of chemoradiotherapy resistance in glioma stem cells (GSCs), enhancing their proliferation and stemness maintenance. Mechanistically, MSN activates the downstream PI3K/mTOR signaling pathway, driving the proneural‐to‐mesenchymal transition (PMT) in GSCs. This process enhances the repair of DNA damage caused by radiotherapy (RT) and temozolomide (TMZ), thereby increasing the resistance of GSCs to chemoradiotherapy. Additionally, GNE‐317, a small molecule drug capable of crossing the blood‐brain barrier, specifically inhibits MSN and suppresses the activation of downstream PI3K/mTOR signaling. Importantly, the combination of GNE‐317 with RT and TMZ exhibits a strong synergistic effect both in vivo and in vitro, achieving better efficacy compared to the traditional combination of RT and TMZ. This study not only advances understanding of the mechanisms underlying chemoradiotherapy resistance in GBM but also provides a promising new approach for enhancing treatment outcomes. |
| format | Article |
| id | doaj-art-ed73086dac2149fbaedada268def6101 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-ed73086dac2149fbaedada268def61012025-08-20T01:49:42ZengWileyAdvanced Science2198-38442025-03-011212n/an/a10.1002/advs.202412517GNE‐317 Reverses MSN‐Mediated Proneural‐to‐Mesenchymal Transition and Suppresses Chemoradiotherapy Resistance in Glioblastoma via PI3K/mTORYong‐Chang Yang0Xing‐Yu Jin1Ling‐Ling Yang2Xing Xu3Yang Xie4Yi‐Ding Ai5Xin‐Chao Li6Ye‐Cheng Ma7Cheng‐Long Xu8Qi Li9Xiang‐Lian Ge10Tai‐Long Yi11Tao Jiang12Xiao‐Guang Wang13Ying‐Zhe Piao14Xun Jin15Department of Biochemistry and Molecular Biology Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin's Clinical Research Center for Cancer Huanhuxi Road, Ti‐Yuan‐Bei Hexi District Tianjin 300060 P. R. ChinaDepartment of Biochemistry and Molecular Biology Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin's Clinical Research Center for Cancer Huanhuxi Road, Ti‐Yuan‐Bei Hexi District Tianjin 300060 P. R. ChinaDepartment of Biochemistry and Molecular Biology Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin's Clinical Research Center for Cancer Huanhuxi Road, Ti‐Yuan‐Bei Hexi District Tianjin 300060 P. R. ChinaDepartment of Biochemistry and Molecular Biology Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin's Clinical Research Center for Cancer Huanhuxi Road, Ti‐Yuan‐Bei Hexi District Tianjin 300060 P. R. ChinaDepartment of Biochemistry and Molecular Biology Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin's Clinical Research Center for Cancer Huanhuxi Road, Ti‐Yuan‐Bei Hexi District Tianjin 300060 P. R. ChinaDepartment of Biochemistry and Molecular Biology Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin's Clinical Research Center for Cancer Huanhuxi Road, Ti‐Yuan‐Bei Hexi District Tianjin 300060 P. R. ChinaDepartment of Biochemistry and Molecular Biology Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin's Clinical Research Center for Cancer Huanhuxi Road, Ti‐Yuan‐Bei Hexi District Tianjin 300060 P. R. ChinaDepartment of Biochemistry and Molecular Biology Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin's Clinical Research Center for Cancer Huanhuxi Road, Ti‐Yuan‐Bei Hexi District Tianjin 300060 P. R. ChinaTianjin Medical University Tianjin 300060 P. R. ChinaTianjin Medical University Tianjin 300060 P. R. ChinaDepartment of Biochemistry and Molecular Biology Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin's Clinical Research Center for Cancer Huanhuxi Road, Ti‐Yuan‐Bei Hexi District Tianjin 300060 P. R. ChinaDepartment of Biochemistry and Molecular Biology Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin's Clinical Research Center for Cancer Huanhuxi Road, Ti‐Yuan‐Bei Hexi District Tianjin 300060 P. R. ChinaBeijing Neurosurgical Institute Capital Medical University Beijing 100054 P. R. ChinaDepartment of Neuro‐Oncology and Neurosurgery Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin 300060 P. R. ChinaDepartment of Neuro‐Oncology and Neurosurgery Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin 300060 P. R. ChinaDepartment of Biochemistry and Molecular Biology Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Tianjin's Clinical Research Center for Cancer Huanhuxi Road, Ti‐Yuan‐Bei Hexi District Tianjin 300060 P. R. ChinaAbstract Glioblastoma (GBM) resistance to chemoradiotherapy is a major factor contributing to poor treatment outcomes. This resistance markedly affects the effectiveness of surgery combined with chemoradiotherapy and leads to post‐surgical tumor recurrence. Therefore, exploring the mechanisms underlying chemoradiotherapy resistance in GBM is crucial for understanding its progression and improving therapeutic options. This study found that moesin (MSN) acts as a key promotor of chemoradiotherapy resistance in glioma stem cells (GSCs), enhancing their proliferation and stemness maintenance. Mechanistically, MSN activates the downstream PI3K/mTOR signaling pathway, driving the proneural‐to‐mesenchymal transition (PMT) in GSCs. This process enhances the repair of DNA damage caused by radiotherapy (RT) and temozolomide (TMZ), thereby increasing the resistance of GSCs to chemoradiotherapy. Additionally, GNE‐317, a small molecule drug capable of crossing the blood‐brain barrier, specifically inhibits MSN and suppresses the activation of downstream PI3K/mTOR signaling. Importantly, the combination of GNE‐317 with RT and TMZ exhibits a strong synergistic effect both in vivo and in vitro, achieving better efficacy compared to the traditional combination of RT and TMZ. This study not only advances understanding of the mechanisms underlying chemoradiotherapy resistance in GBM but also provides a promising new approach for enhancing treatment outcomes.https://doi.org/10.1002/advs.202412517chemoradiotherapy resistanceglioblastomaGNE‐317MSNPI3K/mTORproneural‐to‐mesenchymal transition |
| spellingShingle | Yong‐Chang Yang Xing‐Yu Jin Ling‐Ling Yang Xing Xu Yang Xie Yi‐Ding Ai Xin‐Chao Li Ye‐Cheng Ma Cheng‐Long Xu Qi Li Xiang‐Lian Ge Tai‐Long Yi Tao Jiang Xiao‐Guang Wang Ying‐Zhe Piao Xun Jin GNE‐317 Reverses MSN‐Mediated Proneural‐to‐Mesenchymal Transition and Suppresses Chemoradiotherapy Resistance in Glioblastoma via PI3K/mTOR Advanced Science chemoradiotherapy resistance glioblastoma GNE‐317 MSN PI3K/mTOR proneural‐to‐mesenchymal transition |
| title | GNE‐317 Reverses MSN‐Mediated Proneural‐to‐Mesenchymal Transition and Suppresses Chemoradiotherapy Resistance in Glioblastoma via PI3K/mTOR |
| title_full | GNE‐317 Reverses MSN‐Mediated Proneural‐to‐Mesenchymal Transition and Suppresses Chemoradiotherapy Resistance in Glioblastoma via PI3K/mTOR |
| title_fullStr | GNE‐317 Reverses MSN‐Mediated Proneural‐to‐Mesenchymal Transition and Suppresses Chemoradiotherapy Resistance in Glioblastoma via PI3K/mTOR |
| title_full_unstemmed | GNE‐317 Reverses MSN‐Mediated Proneural‐to‐Mesenchymal Transition and Suppresses Chemoradiotherapy Resistance in Glioblastoma via PI3K/mTOR |
| title_short | GNE‐317 Reverses MSN‐Mediated Proneural‐to‐Mesenchymal Transition and Suppresses Chemoradiotherapy Resistance in Glioblastoma via PI3K/mTOR |
| title_sort | gne 317 reverses msn mediated proneural to mesenchymal transition and suppresses chemoradiotherapy resistance in glioblastoma via pi3k mtor |
| topic | chemoradiotherapy resistance glioblastoma GNE‐317 MSN PI3K/mTOR proneural‐to‐mesenchymal transition |
| url | https://doi.org/10.1002/advs.202412517 |
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