RETRACTED ARTICLE: GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell death
Abstract Glioblastoma multiforme (GBM) is an extremely aggressive brain tumor for which new therapeutic approaches are urgently required. Unfolded protein response (UPR) plays an important role in the progression of GBM and is a promising target for developing novel therapeutic interventions. We ide...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-04023-w |
| _version_ | 1827325959799308288 |
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| author | Guanzheng Liu Jiefeng Yu Runqiu Wu Lin Shi Xu Zhang Wanhong Zhang Xiaomin Zhong Yifeng Wang Huan Li Yang Shen Changyong Wu Rutong Yu Mingshan Niu Xuejiao Liu |
| author_facet | Guanzheng Liu Jiefeng Yu Runqiu Wu Lin Shi Xu Zhang Wanhong Zhang Xiaomin Zhong Yifeng Wang Huan Li Yang Shen Changyong Wu Rutong Yu Mingshan Niu Xuejiao Liu |
| author_sort | Guanzheng Liu |
| collection | DOAJ |
| description | Abstract Glioblastoma multiforme (GBM) is an extremely aggressive brain tumor for which new therapeutic approaches are urgently required. Unfolded protein response (UPR) plays an important role in the progression of GBM and is a promising target for developing novel therapeutic interventions. We identified ubiquitin-activating enzyme 1 (UBA1) inhibitor TAK-243 that can strongly induce UPR in GBM cells. In this study, we evaluated the functional activity and mechanism of TAK-243 in preclinical models of GBM. TAK-243 significantly inhibited the survival, proliferation, and colony formation of GBM cell lines and primary GBM cells. It also revealed a significant anti-tumor effect on a GBM PDX animal model and prolonged the survival time of tumor-bearing mice. Notably, TAK-243 more effectively inhibited the survival and self-renewal ability of glioblastoma stem cells (GSCs) than GBM cells. Importantly, we found that the expression level of GRP78 is a key factor in determining the sensitivity of differentiated GBM cells or GSCs to TAK-243. Mechanistically, UBA1 inhibition disrupts global protein ubiquitination in GBM cells, thereby inducing ER stress and UPR. UPR activates the PERK/ATF4 and IRE1α/XBP signaling axes. These findings indicate that UBA1 inhibition could be an attractive strategy that may be potentially used in the treatment of patients with GBM, and GRP78 can be used as a molecular marker for personalized treatment by targeting UBA1. |
| first_indexed | 2024-03-07T14:37:47Z |
| format | Article |
| id | doaj.art-686657be80554fa58d87c62f380f9f6d |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-07T14:37:47Z |
| publishDate | 2021-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-686657be80554fa58d87c62f380f9f6d2024-03-05T20:31:31ZengNature Publishing GroupCell Death and Disease2041-48892021-07-0112811310.1038/s41419-021-04023-wRETRACTED ARTICLE: GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell deathGuanzheng Liu0Jiefeng Yu1Runqiu Wu2Lin Shi3Xu Zhang4Wanhong Zhang5Xiaomin Zhong6Yifeng Wang7Huan Li8Yang Shen9Changyong Wu10Rutong Yu11Mingshan Niu12Xuejiao Liu13Insititute of Nervous System Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical UniversityInsititute of Nervous System Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical UniversityInsititute of Nervous System Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical UniversityInsititute of Nervous System Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical UniversityDepartment of Neurosurgery, The Affiliated Hospital of Xuzhou Medical UniversityDepartment of Neurosurgery, Kaifeng Central HospitalDepartment of Medical Oncology, Huai’an First People’s Hospital, Nanjing Medical UniversityInsititute of Nervous System Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical UniversityInsititute of Nervous System Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical UniversityInsititute of Nervous System Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical UniversityInsititute of Nervous System Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical UniversityInsititute of Nervous System Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical UniversityInsititute of Nervous System Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical UniversityInsititute of Nervous System Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical UniversityAbstract Glioblastoma multiforme (GBM) is an extremely aggressive brain tumor for which new therapeutic approaches are urgently required. Unfolded protein response (UPR) plays an important role in the progression of GBM and is a promising target for developing novel therapeutic interventions. We identified ubiquitin-activating enzyme 1 (UBA1) inhibitor TAK-243 that can strongly induce UPR in GBM cells. In this study, we evaluated the functional activity and mechanism of TAK-243 in preclinical models of GBM. TAK-243 significantly inhibited the survival, proliferation, and colony formation of GBM cell lines and primary GBM cells. It also revealed a significant anti-tumor effect on a GBM PDX animal model and prolonged the survival time of tumor-bearing mice. Notably, TAK-243 more effectively inhibited the survival and self-renewal ability of glioblastoma stem cells (GSCs) than GBM cells. Importantly, we found that the expression level of GRP78 is a key factor in determining the sensitivity of differentiated GBM cells or GSCs to TAK-243. Mechanistically, UBA1 inhibition disrupts global protein ubiquitination in GBM cells, thereby inducing ER stress and UPR. UPR activates the PERK/ATF4 and IRE1α/XBP signaling axes. These findings indicate that UBA1 inhibition could be an attractive strategy that may be potentially used in the treatment of patients with GBM, and GRP78 can be used as a molecular marker for personalized treatment by targeting UBA1.https://doi.org/10.1038/s41419-021-04023-w |
| spellingShingle | Guanzheng Liu Jiefeng Yu Runqiu Wu Lin Shi Xu Zhang Wanhong Zhang Xiaomin Zhong Yifeng Wang Huan Li Yang Shen Changyong Wu Rutong Yu Mingshan Niu Xuejiao Liu RETRACTED ARTICLE: GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell death Cell Death and Disease |
| title | RETRACTED ARTICLE: GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell death |
| title_full | RETRACTED ARTICLE: GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell death |
| title_fullStr | RETRACTED ARTICLE: GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell death |
| title_full_unstemmed | RETRACTED ARTICLE: GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell death |
| title_short | RETRACTED ARTICLE: GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell death |
| title_sort | retracted article grp78 determines glioblastoma sensitivity to uba1 inhibition induced upr signaling and cell death |
| url | https://doi.org/10.1038/s41419-021-04023-w |
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