Resveratrol Enhances Temozolomide Efficacy in Glioblastoma Cells through Downregulated MGMT and Negative Regulators-Related STAT3 Inactivation
Chemoresistance blunts the efficacy of temozolomide (TMZ) in the treatment of glioblastoma (GBM). Elevated levels of O6-methylguanine-DNA methyltransferase (MGMT) and activation of signal transducer and of transcription 3 (STAT3) have been reported to correlate with GBM resistance to alkylator chemo...
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/11/9453 |
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| author | Moli Wu Danyang Song Hui Li Nisar Ahmad Hong Xu Xiaobo Yang Qian Wang Xiaoxin Cheng Sa Deng Xiaohong Shu |
| author_facet | Moli Wu Danyang Song Hui Li Nisar Ahmad Hong Xu Xiaobo Yang Qian Wang Xiaoxin Cheng Sa Deng Xiaohong Shu |
| author_sort | Moli Wu |
| collection | DOAJ |
| description | Chemoresistance blunts the efficacy of temozolomide (TMZ) in the treatment of glioblastoma (GBM). Elevated levels of O6-methylguanine-DNA methyltransferase (MGMT) and activation of signal transducer and of transcription 3 (STAT3) have been reported to correlate with GBM resistance to alkylator chemotherapy. Resveratrol (Res) inhibits tumor growth and improves drug chemosensitivity by targeting STAT3 signaling. Whether the combined therapy of TMZ and Res could enhance chemosensitivity against GBM cells and the underlying molecular mechanism remains to be determined. In this study, Res was found to effectively improve chemosensitivities of different GBM cells to TMZ, which was evaluated by CCK-8, flow cytometry, and cell migration assay. The combined use of Res and TMZ downregulated STAT3 activity and STAT3-regulated gene products, thus inhibited cell proliferation and migration, as well as induced apoptosis, accompanied by increased levels of its negative regulators: PIAS3, SHP1, SHP2, and SOCS3. More importantly, a combination therapy of Res and TMZ reversed TMZ resistance of LN428 cells, which could be related to decreased MGMT and STAT3 levels. Furthermore, the JAK2-specific inhibitor AG490 was used to demonstrate that a reduced MGMT level was mediated by STAT3 inactivation. Taken together, Res inhibited STAT3 signaling through modulation of PIAS3, SHP1, SHP2, and SOCS3, thereby attenuating tumor growth and increasing sensitivity to TMZ. Therefore, Res is an ideal candidate to be used in TMZ combined chemotherapy for GBM. |
| first_indexed | 2024-03-11T03:05:52Z |
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| id | doaj.art-a2606252e3324cc2a81ce5523f0d98c0 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T03:05:52Z |
| publishDate | 2023-05-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a2606252e3324cc2a81ce5523f0d98c02023-11-18T07:59:14ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012411945310.3390/ijms24119453Resveratrol Enhances Temozolomide Efficacy in Glioblastoma Cells through Downregulated MGMT and Negative Regulators-Related STAT3 InactivationMoli Wu0Danyang Song1Hui Li2Nisar Ahmad3Hong Xu4Xiaobo Yang5Qian Wang6Xiaoxin Cheng7Sa Deng8Xiaohong Shu9College of Pharmacy, Dalian Medical University, Dalian 116044, ChinaCollege of Pharmacy, Dalian Medical University, Dalian 116044, ChinaCollege of Pharmacy, Dalian Medical University, Dalian 116044, ChinaCollege of Pharmacy, Dalian Medical University, Dalian 116044, ChinaCollege of Basic Medical Science, Dalian Medical University, Dalian 116044, ChinaCollege of Pharmacy, Dalian Medical University, Dalian 116044, ChinaCollege of Basic Medical Science, Dalian Medical University, Dalian 116044, ChinaCollege of Basic Medical Science, Dalian Medical University, Dalian 116044, ChinaCollege of Pharmacy, Dalian Medical University, Dalian 116044, ChinaCollege of Pharmacy, Dalian Medical University, Dalian 116044, ChinaChemoresistance blunts the efficacy of temozolomide (TMZ) in the treatment of glioblastoma (GBM). Elevated levels of O6-methylguanine-DNA methyltransferase (MGMT) and activation of signal transducer and of transcription 3 (STAT3) have been reported to correlate with GBM resistance to alkylator chemotherapy. Resveratrol (Res) inhibits tumor growth and improves drug chemosensitivity by targeting STAT3 signaling. Whether the combined therapy of TMZ and Res could enhance chemosensitivity against GBM cells and the underlying molecular mechanism remains to be determined. In this study, Res was found to effectively improve chemosensitivities of different GBM cells to TMZ, which was evaluated by CCK-8, flow cytometry, and cell migration assay. The combined use of Res and TMZ downregulated STAT3 activity and STAT3-regulated gene products, thus inhibited cell proliferation and migration, as well as induced apoptosis, accompanied by increased levels of its negative regulators: PIAS3, SHP1, SHP2, and SOCS3. More importantly, a combination therapy of Res and TMZ reversed TMZ resistance of LN428 cells, which could be related to decreased MGMT and STAT3 levels. Furthermore, the JAK2-specific inhibitor AG490 was used to demonstrate that a reduced MGMT level was mediated by STAT3 inactivation. Taken together, Res inhibited STAT3 signaling through modulation of PIAS3, SHP1, SHP2, and SOCS3, thereby attenuating tumor growth and increasing sensitivity to TMZ. Therefore, Res is an ideal candidate to be used in TMZ combined chemotherapy for GBM.https://www.mdpi.com/1422-0067/24/11/9453glioblastomaresveratroltemozolomideSTAT3STAT3 negative regulatorsMGMT |
| spellingShingle | Moli Wu Danyang Song Hui Li Nisar Ahmad Hong Xu Xiaobo Yang Qian Wang Xiaoxin Cheng Sa Deng Xiaohong Shu Resveratrol Enhances Temozolomide Efficacy in Glioblastoma Cells through Downregulated MGMT and Negative Regulators-Related STAT3 Inactivation International Journal of Molecular Sciences glioblastoma resveratrol temozolomide STAT3 STAT3 negative regulators MGMT |
| title | Resveratrol Enhances Temozolomide Efficacy in Glioblastoma Cells through Downregulated MGMT and Negative Regulators-Related STAT3 Inactivation |
| title_full | Resveratrol Enhances Temozolomide Efficacy in Glioblastoma Cells through Downregulated MGMT and Negative Regulators-Related STAT3 Inactivation |
| title_fullStr | Resveratrol Enhances Temozolomide Efficacy in Glioblastoma Cells through Downregulated MGMT and Negative Regulators-Related STAT3 Inactivation |
| title_full_unstemmed | Resveratrol Enhances Temozolomide Efficacy in Glioblastoma Cells through Downregulated MGMT and Negative Regulators-Related STAT3 Inactivation |
| title_short | Resveratrol Enhances Temozolomide Efficacy in Glioblastoma Cells through Downregulated MGMT and Negative Regulators-Related STAT3 Inactivation |
| title_sort | resveratrol enhances temozolomide efficacy in glioblastoma cells through downregulated mgmt and negative regulators related stat3 inactivation |
| topic | glioblastoma resveratrol temozolomide STAT3 STAT3 negative regulators MGMT |
| url | https://www.mdpi.com/1422-0067/24/11/9453 |
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