Eukaryotic initiation factor 5A2 mediates hypoxia-induced autophagy and cisplatin resistance
Abstract Hypoxia-induced cisplatin resistance is a major challenge during non-small cell lung cancer (NSCLC) treatment. Based on previous studies, we further explored the effect of eukaryotic initiation factor 5A2 (eIF5A2) in hypoxia-induced cisplatin resistance. In this study, we found that autopha...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05033-y |
| _version_ | 1818505486462353408 |
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| author | Guodong Xu Hang Chen Shibo Wu Jiabin Chen Shufen Zhang Guofeng Shao Lebo Sun Yinyu Mu Kaitai Liu Qiaoling Pan Ni Li Xiaoxia An Shuang Lin Wei Chen |
| author_facet | Guodong Xu Hang Chen Shibo Wu Jiabin Chen Shufen Zhang Guofeng Shao Lebo Sun Yinyu Mu Kaitai Liu Qiaoling Pan Ni Li Xiaoxia An Shuang Lin Wei Chen |
| author_sort | Guodong Xu |
| collection | DOAJ |
| description | Abstract Hypoxia-induced cisplatin resistance is a major challenge during non-small cell lung cancer (NSCLC) treatment. Based on previous studies, we further explored the effect of eukaryotic initiation factor 5A2 (eIF5A2) in hypoxia-induced cisplatin resistance. In this study, we found that autophagy and cisplatin resistance were increased under hypoxic conditions in three different NSCLC cell lines. Compared with that under normoxic conditions, dramatic upregulation of eIF5A2 and hypoxia inducible factor 1 subunit alpha (HIF-1α) levels were detected under hypoxia exposure. Small interfering RNA silencing of HIF-1α resulted in decreased expression of eIF5A2, indicating that eIF5A2 acts downstream of HIF-1α. In addition, the expression of eIF5A2 was significantly higher in NSCLC tumors compared with that in normal tissues. RNA silencing-mediated downregulation of eIF5A2 decreased hypoxia-induced autophagy, thereby reducing hypoxia-induced cisplatin resistance in NSCLC cells. The roles of eIF5A2 in cisplatin resistance were further validated in vivo. Combined treatment using eIF5A2-targeted downregulation together with cisplatin significantly inhibited tumor growth compared with cisplatin alone in the subcutaneous mouse model. In conclusions, eIF5A2 overexpression is involved in hypoxia-induced autophagy during cisplatin resistance. We suggest that a combination of eIF5A2 targeted therapy and cisplatin chemotherapy is probably an effective strategy to reverse hypoxia-induced cisplatin resistance and inhibit NSCLC development. |
| first_indexed | 2024-12-10T21:51:26Z |
| format | Article |
| id | doaj.art-03a10ddfc17442589234f33b7d66378e |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-10T21:51:26Z |
| publishDate | 2022-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-03a10ddfc17442589234f33b7d66378e2022-12-22T01:32:11ZengNature Publishing GroupCell Death and Disease2041-48892022-08-0113811110.1038/s41419-022-05033-yEukaryotic initiation factor 5A2 mediates hypoxia-induced autophagy and cisplatin resistanceGuodong Xu0Hang Chen1Shibo Wu2Jiabin Chen3Shufen Zhang4Guofeng Shao5Lebo Sun6Yinyu Mu7Kaitai Liu8Qiaoling Pan9Ni Li10Xiaoxia An11Shuang Lin12Wei Chen13Department of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo UniversityMedical School, Ningbo UniversityDepartment of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo UniversityDepartment of Oncology, Tongde Hospital of Zhejiang ProvinceCancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang ProvinceDepartment of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo UniversityDepartment of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo UniversityDepartment of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo UniversityDepartment of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo UniversityDepartment of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo UniversityDepartment of Cardiothoracic Surgery, the Affiliated Lihuili Hospital, Ningbo UniversityDepartment of Anesthesiology, the First Affiliated Hospital, College of Medicine, Zhejiang UniversityDepartment of Thoracic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang UniversityCancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang ProvinceAbstract Hypoxia-induced cisplatin resistance is a major challenge during non-small cell lung cancer (NSCLC) treatment. Based on previous studies, we further explored the effect of eukaryotic initiation factor 5A2 (eIF5A2) in hypoxia-induced cisplatin resistance. In this study, we found that autophagy and cisplatin resistance were increased under hypoxic conditions in three different NSCLC cell lines. Compared with that under normoxic conditions, dramatic upregulation of eIF5A2 and hypoxia inducible factor 1 subunit alpha (HIF-1α) levels were detected under hypoxia exposure. Small interfering RNA silencing of HIF-1α resulted in decreased expression of eIF5A2, indicating that eIF5A2 acts downstream of HIF-1α. In addition, the expression of eIF5A2 was significantly higher in NSCLC tumors compared with that in normal tissues. RNA silencing-mediated downregulation of eIF5A2 decreased hypoxia-induced autophagy, thereby reducing hypoxia-induced cisplatin resistance in NSCLC cells. The roles of eIF5A2 in cisplatin resistance were further validated in vivo. Combined treatment using eIF5A2-targeted downregulation together with cisplatin significantly inhibited tumor growth compared with cisplatin alone in the subcutaneous mouse model. In conclusions, eIF5A2 overexpression is involved in hypoxia-induced autophagy during cisplatin resistance. We suggest that a combination of eIF5A2 targeted therapy and cisplatin chemotherapy is probably an effective strategy to reverse hypoxia-induced cisplatin resistance and inhibit NSCLC development.https://doi.org/10.1038/s41419-022-05033-y |
| spellingShingle | Guodong Xu Hang Chen Shibo Wu Jiabin Chen Shufen Zhang Guofeng Shao Lebo Sun Yinyu Mu Kaitai Liu Qiaoling Pan Ni Li Xiaoxia An Shuang Lin Wei Chen Eukaryotic initiation factor 5A2 mediates hypoxia-induced autophagy and cisplatin resistance Cell Death and Disease |
| title | Eukaryotic initiation factor 5A2 mediates hypoxia-induced autophagy and cisplatin resistance |
| title_full | Eukaryotic initiation factor 5A2 mediates hypoxia-induced autophagy and cisplatin resistance |
| title_fullStr | Eukaryotic initiation factor 5A2 mediates hypoxia-induced autophagy and cisplatin resistance |
| title_full_unstemmed | Eukaryotic initiation factor 5A2 mediates hypoxia-induced autophagy and cisplatin resistance |
| title_short | Eukaryotic initiation factor 5A2 mediates hypoxia-induced autophagy and cisplatin resistance |
| title_sort | eukaryotic initiation factor 5a2 mediates hypoxia induced autophagy and cisplatin resistance |
| url | https://doi.org/10.1038/s41419-022-05033-y |
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