Morusin Enhances Temozolomide Efficiency in GBM by Inducing Cytoplasmic Vacuolization and Endoplasmic Reticulum Stress
Glioblastoma multiforme (GBM) is an aggressive brain tumor with high risks of recurrence and mortality. Chemoradiotherapy resistance has been considered a major factor contributing to the extremely poor prognosis of GBM patients. Therefore, there is an urgent need to develop highly effective therape...
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MDPI AG
2022-06-01
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| Series: | Journal of Clinical Medicine |
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| Online Access: | https://www.mdpi.com/2077-0383/11/13/3662 |
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| author | Rongchuan Zhao Yuanshuai Zhou Hong Zhang Jinlin Pan Fan Yang Ruobing Zhang Nafees Ahmad Jiao Yang Minxuan Sun |
| author_facet | Rongchuan Zhao Yuanshuai Zhou Hong Zhang Jinlin Pan Fan Yang Ruobing Zhang Nafees Ahmad Jiao Yang Minxuan Sun |
| author_sort | Rongchuan Zhao |
| collection | DOAJ |
| description | Glioblastoma multiforme (GBM) is an aggressive brain tumor with high risks of recurrence and mortality. Chemoradiotherapy resistance has been considered a major factor contributing to the extremely poor prognosis of GBM patients. Therefore, there is an urgent need to develop highly effective therapeutic agents. Here, we demonstrate the anti-tumor effect of morusin, a typical prenylated flavonoid, in GBM through in vivo and in vitro models. Morusin showed selective cytotoxicity toward GBM cell lines without harming normal human astrocytes when the concentration was less than 20 µM. Morusin treatment significantly induced apoptosis of GBM cells, accompanied by the activation of endoplasmic reticulum (ER) stress, and the appearance of cytoplasmic vacuolation and autophagosomes in cells. Then, we found the ER stress activation and cytotoxicity of morusin were rescued by ER stress inhibitor 4-PBA. Furthermore, morusin arrested cell cycle at the G1 phase and inhibited cell proliferation of GBM cells through the Akt–mTOR–p70S6K pathway. Dysregulation of ERs and cell cycle in morusin exposed GBM cells were confirmed by RNA-seq analysis. Finally, we demonstrated the combination of morusin and TMZ remarkably enhanced ER stress and displayed a synergistic effect in GBM cells, and suppressed tumor progression in an orthotopic xenograft model. In conclusion, these findings reveal the toxicity of morusin to GBM cells and its ability to enhance drug sensitivity to TMZ, suggesting the potential application value of morusin in the development of therapeutic strategies for human GBM. |
| first_indexed | 2024-03-09T04:05:25Z |
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| issn | 2077-0383 |
| language | English |
| last_indexed | 2024-03-09T04:05:25Z |
| publishDate | 2022-06-01 |
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| record_format | Article |
| series | Journal of Clinical Medicine |
| spelling | doaj.art-572afb998f9f456d8077ea134cab04cd2023-12-03T14:07:28ZengMDPI AGJournal of Clinical Medicine2077-03832022-06-011113366210.3390/jcm11133662Morusin Enhances Temozolomide Efficiency in GBM by Inducing Cytoplasmic Vacuolization and Endoplasmic Reticulum StressRongchuan Zhao0Yuanshuai Zhou1Hong Zhang2Jinlin Pan3Fan Yang4Ruobing Zhang5Nafees Ahmad6Jiao Yang7Minxuan Sun8Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, ChinaSchool of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, ChinaSchool of Life Sciences, Shanghai University, Shanghai 200444, ChinaSuzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, ChinaSchool of Life Sciences, Shanghai University, Shanghai 200444, ChinaSuzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, ChinaInstitute of Biomedical and Genetic Engineering, Islamabad 44000, PakistanInstitute of Clinical Medicine Research, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou 215163, ChinaSuzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, ChinaGlioblastoma multiforme (GBM) is an aggressive brain tumor with high risks of recurrence and mortality. Chemoradiotherapy resistance has been considered a major factor contributing to the extremely poor prognosis of GBM patients. Therefore, there is an urgent need to develop highly effective therapeutic agents. Here, we demonstrate the anti-tumor effect of morusin, a typical prenylated flavonoid, in GBM through in vivo and in vitro models. Morusin showed selective cytotoxicity toward GBM cell lines without harming normal human astrocytes when the concentration was less than 20 µM. Morusin treatment significantly induced apoptosis of GBM cells, accompanied by the activation of endoplasmic reticulum (ER) stress, and the appearance of cytoplasmic vacuolation and autophagosomes in cells. Then, we found the ER stress activation and cytotoxicity of morusin were rescued by ER stress inhibitor 4-PBA. Furthermore, morusin arrested cell cycle at the G1 phase and inhibited cell proliferation of GBM cells through the Akt–mTOR–p70S6K pathway. Dysregulation of ERs and cell cycle in morusin exposed GBM cells were confirmed by RNA-seq analysis. Finally, we demonstrated the combination of morusin and TMZ remarkably enhanced ER stress and displayed a synergistic effect in GBM cells, and suppressed tumor progression in an orthotopic xenograft model. In conclusion, these findings reveal the toxicity of morusin to GBM cells and its ability to enhance drug sensitivity to TMZ, suggesting the potential application value of morusin in the development of therapeutic strategies for human GBM.https://www.mdpi.com/2077-0383/11/13/3662glioblastoma multiformemorusincytoplasmic vacuolationendoplasmic reticulum stresstumor progression |
| spellingShingle | Rongchuan Zhao Yuanshuai Zhou Hong Zhang Jinlin Pan Fan Yang Ruobing Zhang Nafees Ahmad Jiao Yang Minxuan Sun Morusin Enhances Temozolomide Efficiency in GBM by Inducing Cytoplasmic Vacuolization and Endoplasmic Reticulum Stress Journal of Clinical Medicine glioblastoma multiforme morusin cytoplasmic vacuolation endoplasmic reticulum stress tumor progression |
| title | Morusin Enhances Temozolomide Efficiency in GBM by Inducing Cytoplasmic Vacuolization and Endoplasmic Reticulum Stress |
| title_full | Morusin Enhances Temozolomide Efficiency in GBM by Inducing Cytoplasmic Vacuolization and Endoplasmic Reticulum Stress |
| title_fullStr | Morusin Enhances Temozolomide Efficiency in GBM by Inducing Cytoplasmic Vacuolization and Endoplasmic Reticulum Stress |
| title_full_unstemmed | Morusin Enhances Temozolomide Efficiency in GBM by Inducing Cytoplasmic Vacuolization and Endoplasmic Reticulum Stress |
| title_short | Morusin Enhances Temozolomide Efficiency in GBM by Inducing Cytoplasmic Vacuolization and Endoplasmic Reticulum Stress |
| title_sort | morusin enhances temozolomide efficiency in gbm by inducing cytoplasmic vacuolization and endoplasmic reticulum stress |
| topic | glioblastoma multiforme morusin cytoplasmic vacuolation endoplasmic reticulum stress tumor progression |
| url | https://www.mdpi.com/2077-0383/11/13/3662 |
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