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GRP78 blockade overcomes intrinsic resistance to UBA1 inhibitor TAK-243 in glioblastoma

Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor of the central nervous system. Despite continuous progression in treatment options for GBM like surgery, radiotherapy, and chemotherapy, this disease still has a high rate of recurrence. The endoplasmic reticulum (ER)...

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Autores principales: Zhang, Xu, Wu, Runqiu, Tian, Cong, Wang, Wanzhou, Zhou, Lingni, Guo, Tongxuan, Yu, Jiefeng, Wu, Changyong, Shen, Yang, Liu, Xuejiao, Yu, Rutong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8960808/
https://www.ncbi.nlm.nih.gov/pubmed/35347123
http://dx.doi.org/10.1038/s41420-022-00950-5
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author Zhang, Xu
Wu, Runqiu
Tian, Cong
Wang, Wanzhou
Zhou, Lingni
Guo, Tongxuan
Yu, Jiefeng
Wu, Changyong
Shen, Yang
Liu, Xuejiao
Yu, Rutong
author_facet Zhang, Xu
Wu, Runqiu
Tian, Cong
Wang, Wanzhou
Zhou, Lingni
Guo, Tongxuan
Yu, Jiefeng
Wu, Changyong
Shen, Yang
Liu, Xuejiao
Yu, Rutong
author_sort Zhang, Xu
collection PubMed
description Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor of the central nervous system. Despite continuous progression in treatment options for GBM like surgery, radiotherapy, and chemotherapy, this disease still has a high rate of recurrence. The endoplasmic reticulum (ER) stress pathway is associated with chemotherapeutic drug resistance. The UBA1 inhibitor TAK-243 can induce strong ER stress. However, the sensitivity of TAK-243 varies greatly in different tumor cells. This study evaluated the antitumor effects of the GRP78 inhibitor, HA15, combined with TAK-243 on GBM in the preclinical models. HA15 synergistically enhanced the sensitivity of GBM cells to TAK-243. When compared with TAK-243 monotherapy, HA15 combined with TAK-243 significantly inhibited GBM cell proliferation. It also induced G2/M-phase arrest in the cell cycle. In vivo studies showed that HA15 combined with TAK-243 significantly inhibited the growth of intracranial GBM and prolonged survival of the tumor-bearing mice. Mechanistically, HA15 and TAK-243 synergistically activated the PERK/ATF4 and IRE1α/XBP1 signaling axes, thereby eventually activating PARP and the Caspase families, which induced cell apoptosis. Our data provided a new strategy for improving the sensitivity of GBM to TAK-243 treatment and experimental basis for further clinical trials to evaluate this combination therapy.
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spelling pubmed-89608082022-04-12 GRP78 blockade overcomes intrinsic resistance to UBA1 inhibitor TAK-243 in glioblastoma Zhang, Xu Wu, Runqiu Tian, Cong Wang, Wanzhou Zhou, Lingni Guo, Tongxuan Yu, Jiefeng Wu, Changyong Shen, Yang Liu, Xuejiao Yu, Rutong Cell Death Discov Article Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor of the central nervous system. Despite continuous progression in treatment options for GBM like surgery, radiotherapy, and chemotherapy, this disease still has a high rate of recurrence. The endoplasmic reticulum (ER) stress pathway is associated with chemotherapeutic drug resistance. The UBA1 inhibitor TAK-243 can induce strong ER stress. However, the sensitivity of TAK-243 varies greatly in different tumor cells. This study evaluated the antitumor effects of the GRP78 inhibitor, HA15, combined with TAK-243 on GBM in the preclinical models. HA15 synergistically enhanced the sensitivity of GBM cells to TAK-243. When compared with TAK-243 monotherapy, HA15 combined with TAK-243 significantly inhibited GBM cell proliferation. It also induced G2/M-phase arrest in the cell cycle. In vivo studies showed that HA15 combined with TAK-243 significantly inhibited the growth of intracranial GBM and prolonged survival of the tumor-bearing mice. Mechanistically, HA15 and TAK-243 synergistically activated the PERK/ATF4 and IRE1α/XBP1 signaling axes, thereby eventually activating PARP and the Caspase families, which induced cell apoptosis. Our data provided a new strategy for improving the sensitivity of GBM to TAK-243 treatment and experimental basis for further clinical trials to evaluate this combination therapy. Nature Publishing Group UK 2022-03-28 /pmc/articles/PMC8960808/ /pubmed/35347123 http://dx.doi.org/10.1038/s41420-022-00950-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhang, Xu
Wu, Runqiu
Tian, Cong
Wang, Wanzhou
Zhou, Lingni
Guo, Tongxuan
Yu, Jiefeng
Wu, Changyong
Shen, Yang
Liu, Xuejiao
Yu, Rutong
GRP78 blockade overcomes intrinsic resistance to UBA1 inhibitor TAK-243 in glioblastoma
title GRP78 blockade overcomes intrinsic resistance to UBA1 inhibitor TAK-243 in glioblastoma
title_full GRP78 blockade overcomes intrinsic resistance to UBA1 inhibitor TAK-243 in glioblastoma
title_fullStr GRP78 blockade overcomes intrinsic resistance to UBA1 inhibitor TAK-243 in glioblastoma
title_full_unstemmed GRP78 blockade overcomes intrinsic resistance to UBA1 inhibitor TAK-243 in glioblastoma
title_short GRP78 blockade overcomes intrinsic resistance to UBA1 inhibitor TAK-243 in glioblastoma
title_sort grp78 blockade overcomes intrinsic resistance to uba1 inhibitor tak-243 in glioblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8960808/
https://www.ncbi.nlm.nih.gov/pubmed/35347123
http://dx.doi.org/10.1038/s41420-022-00950-5
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