Valtrate, an iridoid compound in Valeriana, elicits anti-glioblastoma activity through inhibition of the PDGFRA/MEK/ERK signaling pathway
Abstract Background Valtrate, a natural compound isolated from the root of Valeriana, exhibits antitumor activity in many cancers through different mechanisms. However, its efficacy for the treatment of glioblastoma (GBM), a tumor type with a poor prognosis, has not yet been rigorously investigated....
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-02-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-03984-0 |
| _version_ | 1797863672957108224 |
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| author | Xuemeng Liu Yaotian Hu Zhiyi Xue Xun Zhang Xiaofei Liu Guowei Liu Muzi Wen Anjing Chen Bin Huang Xingang Li Ning Yang Jian Wang |
| author_facet | Xuemeng Liu Yaotian Hu Zhiyi Xue Xun Zhang Xiaofei Liu Guowei Liu Muzi Wen Anjing Chen Bin Huang Xingang Li Ning Yang Jian Wang |
| author_sort | Xuemeng Liu |
| collection | DOAJ |
| description | Abstract Background Valtrate, a natural compound isolated from the root of Valeriana, exhibits antitumor activity in many cancers through different mechanisms. However, its efficacy for the treatment of glioblastoma (GBM), a tumor type with a poor prognosis, has not yet been rigorously investigated. Methods GBM cell lines were treated with valtrate and CCK-8, colony formation and EdU assays, flow cytometry, and transwell, 3D tumor spheroid invasion and GBM-brain organoid co-culture invasion assays were performed to assess properties of proliferation, viability, apoptosis and invasion/migration. RNA sequencing analysis on valtrate-treated cells was performed to identify putative target genes underlying the antitumor activity of the drug in GBM cells. Western blot analysis, immunofluorescence and immunohistochemistry were performed to evaluate protein levels in valtrate-treated cell lines and in samples obtained from orthotopic xenografts. A specific activator of extracellular signal-regulated kinase (ERK) was used to identify the pathways mediating the effect. Results Valtrate significantly inhibited the proliferation of GBM cells in vitro by inducing mitochondrial apoptosis and suppressed invasion and migration of GBM cells by inhibiting levels of proteins associated with epithelial mesenchymal transition (EMT). RNA sequencing analysis of valtrate-treated GBM cells revealed platelet-derived growth factor receptor A (PDGFRA) as a potential target downregulated by the drug. Analysis of PDGFRA protein and downstream mediators demonstrated that valtrate inhibited PDGFRA/MEK/ERK signaling. Finally, treatment of tumor-bearing nude mice with valtrate led to decreased tumor volume (fivefold difference at day 28) and enhanced survival (day 27 vs day 36, control vs valtrate-treated) relative to controls. Conclusions Taken together, our study demonstrated that the natural product valtrate elicits antitumor activity in GBM cells through targeting PDGFRA and thus provides a candidate therapeutic compound for the treatment of GBM. |
| first_indexed | 2024-04-09T22:40:26Z |
| format | Article |
| id | doaj.art-5c04398ad17f4818890634457720c92b |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-09T22:40:26Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-5c04398ad17f4818890634457720c92b2023-03-22T12:13:56ZengBMCJournal of Translational Medicine1479-58762023-02-0121111910.1186/s12967-023-03984-0Valtrate, an iridoid compound in Valeriana, elicits anti-glioblastoma activity through inhibition of the PDGFRA/MEK/ERK signaling pathwayXuemeng Liu0Yaotian Hu1Zhiyi Xue2Xun Zhang3Xiaofei Liu4Guowei Liu5Muzi Wen6Anjing Chen7Bin Huang8Xingang Li9Ning Yang10Jian Wang11Department of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong UniversityDepartment of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong UniversityDepartment of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong UniversityDepartment of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong UniversityDepartment of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong UniversityDepartment of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong UniversitySchool of Public Health, Southern Medical UniversityDepartment of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong UniversityDepartment of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong UniversityDepartment of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong UniversityDepartment of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong UniversityDepartment of Neurosurgery, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Qilu Hospital, Shandong UniversityAbstract Background Valtrate, a natural compound isolated from the root of Valeriana, exhibits antitumor activity in many cancers through different mechanisms. However, its efficacy for the treatment of glioblastoma (GBM), a tumor type with a poor prognosis, has not yet been rigorously investigated. Methods GBM cell lines were treated with valtrate and CCK-8, colony formation and EdU assays, flow cytometry, and transwell, 3D tumor spheroid invasion and GBM-brain organoid co-culture invasion assays were performed to assess properties of proliferation, viability, apoptosis and invasion/migration. RNA sequencing analysis on valtrate-treated cells was performed to identify putative target genes underlying the antitumor activity of the drug in GBM cells. Western blot analysis, immunofluorescence and immunohistochemistry were performed to evaluate protein levels in valtrate-treated cell lines and in samples obtained from orthotopic xenografts. A specific activator of extracellular signal-regulated kinase (ERK) was used to identify the pathways mediating the effect. Results Valtrate significantly inhibited the proliferation of GBM cells in vitro by inducing mitochondrial apoptosis and suppressed invasion and migration of GBM cells by inhibiting levels of proteins associated with epithelial mesenchymal transition (EMT). RNA sequencing analysis of valtrate-treated GBM cells revealed platelet-derived growth factor receptor A (PDGFRA) as a potential target downregulated by the drug. Analysis of PDGFRA protein and downstream mediators demonstrated that valtrate inhibited PDGFRA/MEK/ERK signaling. Finally, treatment of tumor-bearing nude mice with valtrate led to decreased tumor volume (fivefold difference at day 28) and enhanced survival (day 27 vs day 36, control vs valtrate-treated) relative to controls. Conclusions Taken together, our study demonstrated that the natural product valtrate elicits antitumor activity in GBM cells through targeting PDGFRA and thus provides a candidate therapeutic compound for the treatment of GBM.https://doi.org/10.1186/s12967-023-03984-0ValtrateGlioblastomaMitochondrial apoptosisEpithelial mesenchymal transitionInvasion and migrationPDGFRA |
| spellingShingle | Xuemeng Liu Yaotian Hu Zhiyi Xue Xun Zhang Xiaofei Liu Guowei Liu Muzi Wen Anjing Chen Bin Huang Xingang Li Ning Yang Jian Wang Valtrate, an iridoid compound in Valeriana, elicits anti-glioblastoma activity through inhibition of the PDGFRA/MEK/ERK signaling pathway Journal of Translational Medicine Valtrate Glioblastoma Mitochondrial apoptosis Epithelial mesenchymal transition Invasion and migration PDGFRA |
| title | Valtrate, an iridoid compound in Valeriana, elicits anti-glioblastoma activity through inhibition of the PDGFRA/MEK/ERK signaling pathway |
| title_full | Valtrate, an iridoid compound in Valeriana, elicits anti-glioblastoma activity through inhibition of the PDGFRA/MEK/ERK signaling pathway |
| title_fullStr | Valtrate, an iridoid compound in Valeriana, elicits anti-glioblastoma activity through inhibition of the PDGFRA/MEK/ERK signaling pathway |
| title_full_unstemmed | Valtrate, an iridoid compound in Valeriana, elicits anti-glioblastoma activity through inhibition of the PDGFRA/MEK/ERK signaling pathway |
| title_short | Valtrate, an iridoid compound in Valeriana, elicits anti-glioblastoma activity through inhibition of the PDGFRA/MEK/ERK signaling pathway |
| title_sort | valtrate an iridoid compound in valeriana elicits anti glioblastoma activity through inhibition of the pdgfra mek erk signaling pathway |
| topic | Valtrate Glioblastoma Mitochondrial apoptosis Epithelial mesenchymal transition Invasion and migration PDGFRA |
| url | https://doi.org/10.1186/s12967-023-03984-0 |
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