Hypoxic microenvironment-induced exosomes confer temozolomide resistance in glioma through transfer of pyruvate kinase M2
Abstract Objective Glioma, a malignant primary brain tumor, is notorious for its high incidence rate. However, the clinical application of temozolomide (TMZ) as a treatment option for glioma is often limited due to resistance, which has been linked to hypoxic glioma cell-released exosomes. In light...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer
2024-04-01
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| Series: | Discover Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s12672-024-00963-9 |
| _version_ | 1797209277088137216 |
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| author | Guofu Li Ziyu Xiong Ying Li Cong Yan Yingying Cheng Yuwen Wang Jingwei Li Zifeng Dai Dongdong Zhang Wenzhong Du Chunyang Men Changbin Shi |
| author_facet | Guofu Li Ziyu Xiong Ying Li Cong Yan Yingying Cheng Yuwen Wang Jingwei Li Zifeng Dai Dongdong Zhang Wenzhong Du Chunyang Men Changbin Shi |
| author_sort | Guofu Li |
| collection | DOAJ |
| description | Abstract Objective Glioma, a malignant primary brain tumor, is notorious for its high incidence rate. However, the clinical application of temozolomide (TMZ) as a treatment option for glioma is often limited due to resistance, which has been linked to hypoxic glioma cell-released exosomes. In light of this, the present study aimed to investigate the role of exosomal pyruvate kinase M2 (PKM2) in glioma cells that exhibit resistance to TMZ. Methods Sensitive and TMZ-resistant glioma cells were subjected to either a normoxic or hypoxic environment, and the growth patterns and enzymatic activity of glycolysis enzymes were subsequently measured. From these cells, exosomal PKM2 was isolated and the subsequent effect on TMZ resistance was examined and characterized, with a particular focus on understanding the relevant mechanisms. Furthermore, the intercellular communication between hypoxic resistant cells and tumor-associated macrophages (TAMs) via exosomal PKM2 was also assessed. Results The adverse impact of hypoxic microenvironments on TMZ resistance in glioma cells was identified and characterized. Among the three glycolysis enzymes that were examined, PKM2 was found to be a critical mediator in hypoxia-triggered TMZ resistance. Upregulation of PKM2 was found to exacerbate the hypoxia-mediated TMZ resistance. Exosomal PKM2 were identified and isolated from hypoxic TMZ-resistant glioma cells, and were found to be responsible for transmitting TMZ resistance to sensitive glioma cells. The exosomal PKM2 also contributed towards mitigating TMZ-induced apoptosis in sensitive glioma cells, while also causing intracellular ROS accumulation. Additionally, hypoxic resistant cells also released exosomal PKM2, which facilitated TMZ resistance in tumor-associated macrophages. Conclusion In the hypoxic microenvironment, glioma cells become resistant to TMZ due to the delivery of PKM2 by exosomes. Targeted modulation of exosomal PKM2 may be a promising strategy for overcoming TMZ resistance in glioma. |
| first_indexed | 2024-04-24T09:52:08Z |
| format | Article |
| id | doaj.art-56facc1dd2104f77bdb51978261e6b47 |
| institution | Directory Open Access Journal |
| issn | 2730-6011 |
| language | English |
| last_indexed | 2024-04-24T09:52:08Z |
| publishDate | 2024-04-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Oncology |
| spelling | doaj.art-56facc1dd2104f77bdb51978261e6b472024-04-14T11:20:07ZengSpringerDiscover Oncology2730-60112024-04-0115111810.1007/s12672-024-00963-9Hypoxic microenvironment-induced exosomes confer temozolomide resistance in glioma through transfer of pyruvate kinase M2Guofu Li0Ziyu Xiong1Ying Li2Cong Yan3Yingying Cheng4Yuwen Wang5Jingwei Li6Zifeng Dai7Dongdong Zhang8Wenzhong Du9Chunyang Men10Changbin Shi11Department of Neurosurgery, Harbin Medical University Cancer HospitalDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Ultrasound, Harbin Medical University Cancer HospitalDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Harbin Medical UniversityAbstract Objective Glioma, a malignant primary brain tumor, is notorious for its high incidence rate. However, the clinical application of temozolomide (TMZ) as a treatment option for glioma is often limited due to resistance, which has been linked to hypoxic glioma cell-released exosomes. In light of this, the present study aimed to investigate the role of exosomal pyruvate kinase M2 (PKM2) in glioma cells that exhibit resistance to TMZ. Methods Sensitive and TMZ-resistant glioma cells were subjected to either a normoxic or hypoxic environment, and the growth patterns and enzymatic activity of glycolysis enzymes were subsequently measured. From these cells, exosomal PKM2 was isolated and the subsequent effect on TMZ resistance was examined and characterized, with a particular focus on understanding the relevant mechanisms. Furthermore, the intercellular communication between hypoxic resistant cells and tumor-associated macrophages (TAMs) via exosomal PKM2 was also assessed. Results The adverse impact of hypoxic microenvironments on TMZ resistance in glioma cells was identified and characterized. Among the three glycolysis enzymes that were examined, PKM2 was found to be a critical mediator in hypoxia-triggered TMZ resistance. Upregulation of PKM2 was found to exacerbate the hypoxia-mediated TMZ resistance. Exosomal PKM2 were identified and isolated from hypoxic TMZ-resistant glioma cells, and were found to be responsible for transmitting TMZ resistance to sensitive glioma cells. The exosomal PKM2 also contributed towards mitigating TMZ-induced apoptosis in sensitive glioma cells, while also causing intracellular ROS accumulation. Additionally, hypoxic resistant cells also released exosomal PKM2, which facilitated TMZ resistance in tumor-associated macrophages. Conclusion In the hypoxic microenvironment, glioma cells become resistant to TMZ due to the delivery of PKM2 by exosomes. Targeted modulation of exosomal PKM2 may be a promising strategy for overcoming TMZ resistance in glioma.https://doi.org/10.1007/s12672-024-00963-9GliomaHypoxiaExosomePyruvate kinase M2TemozolomideResistance |
| spellingShingle | Guofu Li Ziyu Xiong Ying Li Cong Yan Yingying Cheng Yuwen Wang Jingwei Li Zifeng Dai Dongdong Zhang Wenzhong Du Chunyang Men Changbin Shi Hypoxic microenvironment-induced exosomes confer temozolomide resistance in glioma through transfer of pyruvate kinase M2 Discover Oncology Glioma Hypoxia Exosome Pyruvate kinase M2 Temozolomide Resistance |
| title | Hypoxic microenvironment-induced exosomes confer temozolomide resistance in glioma through transfer of pyruvate kinase M2 |
| title_full | Hypoxic microenvironment-induced exosomes confer temozolomide resistance in glioma through transfer of pyruvate kinase M2 |
| title_fullStr | Hypoxic microenvironment-induced exosomes confer temozolomide resistance in glioma through transfer of pyruvate kinase M2 |
| title_full_unstemmed | Hypoxic microenvironment-induced exosomes confer temozolomide resistance in glioma through transfer of pyruvate kinase M2 |
| title_short | Hypoxic microenvironment-induced exosomes confer temozolomide resistance in glioma through transfer of pyruvate kinase M2 |
| title_sort | hypoxic microenvironment induced exosomes confer temozolomide resistance in glioma through transfer of pyruvate kinase m2 |
| topic | Glioma Hypoxia Exosome Pyruvate kinase M2 Temozolomide Resistance |
| url | https://doi.org/10.1007/s12672-024-00963-9 |
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