Gastrodin overcomes chemoresistance via inhibiting Skp2-mediated glycolysis
Abstract Aerobic glycolysis, a typical phenotype in human tumors, is associated with tumor progression and chemotherapy resistance. The present study demonstrated that cisplatin-resistant oral squamous cell carcinoma (OSCC) cells exerted a stronger glycolysis ability, which was associated with hexok...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-10-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01648-y |
| _version_ | 1797453917879009280 |
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| author | Li Xie Jinzhuang Liao Wenbin Liu Ruirui Wang Xiaoying Li Wei Li Zhongsu Zhou |
| author_facet | Li Xie Jinzhuang Liao Wenbin Liu Ruirui Wang Xiaoying Li Wei Li Zhongsu Zhou |
| author_sort | Li Xie |
| collection | DOAJ |
| description | Abstract Aerobic glycolysis, a typical phenotype in human tumors, is associated with tumor progression and chemotherapy resistance. The present study demonstrated that cisplatin-resistant oral squamous cell carcinoma (OSCC) cells exerted a stronger glycolysis ability, which was associated with hexokinase 2 (HK2) overexpression. Additionally, the tumor growth of OSCC cells was delayed in vivo and the glycolysis was notably decreased following HK2 knockdown. The natural compound screening revealed that gastrodin could be an effective candidate for OSCC therapy since it inhibited HK2-mediated glucose metabolism and promoted endogenous OSCC cell apoptosis. Furthermore, gastrodin could bind to protein kinase B (Akt) and suppress its activity, thus downregulating HK2 at the transcriptional level. Additionally, S-phase kinase-associated protein 2 (Skp2) was highly expressed in OSCC cells, while K63-linked ubiquitination of Akt was inhibited in Skp2-depleted cisplatin-resistant OSCC cells. Gastrodin could also inhibit the cisplatin resistance of OSCC cells in vivo, particularly when combined with the Skp2 inhibitor, SZL P1-41. Overall, the aforementioned finding suggested that targeting the Skp2-Akt axis could be a potential therapeutic strategy for treating OSCC and overcoming chemoresistance. |
| first_indexed | 2024-03-09T15:29:47Z |
| format | Article |
| id | doaj.art-fcda82d0268b43819d1fe00706fa9062 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-09T15:29:47Z |
| publishDate | 2023-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-fcda82d0268b43819d1fe00706fa90622023-11-26T12:21:21ZengNature Publishing GroupCell Death Discovery2058-77162023-10-019111310.1038/s41420-023-01648-yGastrodin overcomes chemoresistance via inhibiting Skp2-mediated glycolysisLi Xie0Jinzhuang Liao1Wenbin Liu2Ruirui Wang3Xiaoying Li4Wei Li5Zhongsu Zhou6Department of Head and Neck Surgery, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityDepartment of Radiology, The Third Xiangya Hospital, Central South UniversityDepartment of Pathology, Hunan Cancer HospitalDepartment of Radiology, The Third Xiangya Hospital, Central South UniversityDepartment of Radiology, The Third Xiangya Hospital, Central South UniversityDepartment of Radiology, The Third Xiangya Hospital, Central South UniversityThe Third Hospital of ChangshaAbstract Aerobic glycolysis, a typical phenotype in human tumors, is associated with tumor progression and chemotherapy resistance. The present study demonstrated that cisplatin-resistant oral squamous cell carcinoma (OSCC) cells exerted a stronger glycolysis ability, which was associated with hexokinase 2 (HK2) overexpression. Additionally, the tumor growth of OSCC cells was delayed in vivo and the glycolysis was notably decreased following HK2 knockdown. The natural compound screening revealed that gastrodin could be an effective candidate for OSCC therapy since it inhibited HK2-mediated glucose metabolism and promoted endogenous OSCC cell apoptosis. Furthermore, gastrodin could bind to protein kinase B (Akt) and suppress its activity, thus downregulating HK2 at the transcriptional level. Additionally, S-phase kinase-associated protein 2 (Skp2) was highly expressed in OSCC cells, while K63-linked ubiquitination of Akt was inhibited in Skp2-depleted cisplatin-resistant OSCC cells. Gastrodin could also inhibit the cisplatin resistance of OSCC cells in vivo, particularly when combined with the Skp2 inhibitor, SZL P1-41. Overall, the aforementioned finding suggested that targeting the Skp2-Akt axis could be a potential therapeutic strategy for treating OSCC and overcoming chemoresistance.https://doi.org/10.1038/s41420-023-01648-y |
| spellingShingle | Li Xie Jinzhuang Liao Wenbin Liu Ruirui Wang Xiaoying Li Wei Li Zhongsu Zhou Gastrodin overcomes chemoresistance via inhibiting Skp2-mediated glycolysis Cell Death Discovery |
| title | Gastrodin overcomes chemoresistance via inhibiting Skp2-mediated glycolysis |
| title_full | Gastrodin overcomes chemoresistance via inhibiting Skp2-mediated glycolysis |
| title_fullStr | Gastrodin overcomes chemoresistance via inhibiting Skp2-mediated glycolysis |
| title_full_unstemmed | Gastrodin overcomes chemoresistance via inhibiting Skp2-mediated glycolysis |
| title_short | Gastrodin overcomes chemoresistance via inhibiting Skp2-mediated glycolysis |
| title_sort | gastrodin overcomes chemoresistance via inhibiting skp2 mediated glycolysis |
| url | https://doi.org/10.1038/s41420-023-01648-y |
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