Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling
Abstract Ciclopirox (CPX) is an antifungal drug that has recently been reported to act as a potential anticancer drug. However, the effects and underlying molecular mechanisms of CPX on glioblastoma multiforme (GBM) remain unknown. Bortezomib (BTZ) is the first proteasome inhibitor-based anticancer...
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Format: | Article |
Language: | English |
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Nature Publishing Group
2021-03-01
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Series: | Cell Death and Disease |
Online Access: | https://doi.org/10.1038/s41419-021-03535-9 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zhipeng Su Shengnan Han Qiumei Jin Ningning Zhou Junwan Lu Fugen Shangguan Shiyi Yu Yongzhang Liu Lu Wang Jianglong Lu Qun Li Lin Cai Chengde Wang Xiaohe Tian Lingyan Chen Weiming Zheng Bin Lu |
spellingShingle |
Zhipeng Su Shengnan Han Qiumei Jin Ningning Zhou Junwan Lu Fugen Shangguan Shiyi Yu Yongzhang Liu Lu Wang Jianglong Lu Qun Li Lin Cai Chengde Wang Xiaohe Tian Lingyan Chen Weiming Zheng Bin Lu Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling Cell Death and Disease |
author_facet |
Zhipeng Su Shengnan Han Qiumei Jin Ningning Zhou Junwan Lu Fugen Shangguan Shiyi Yu Yongzhang Liu Lu Wang Jianglong Lu Qun Li Lin Cai Chengde Wang Xiaohe Tian Lingyan Chen Weiming Zheng Bin Lu |
author_sort |
Zhipeng Su |
title |
Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling |
title_short |
Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling |
title_full |
Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling |
title_fullStr |
Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling |
title_full_unstemmed |
Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling |
title_sort |
ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing jnk/p38 mapk and nf-κb signaling |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-03-01 |
description |
Abstract Ciclopirox (CPX) is an antifungal drug that has recently been reported to act as a potential anticancer drug. However, the effects and underlying molecular mechanisms of CPX on glioblastoma multiforme (GBM) remain unknown. Bortezomib (BTZ) is the first proteasome inhibitor-based anticancer drug approved to treat multiple myeloma and mantle cell lymphoma, as BTZ exhibits toxic effects on diverse tumor cells. Herein, we show that CPX displays strong anti-tumorigenic activity on GBM. Mechanistically, CPX inhibits GBM cellular migration and invasion by reducing N-Cadherin, MMP9 and Snail expression. Further analysis revealed that CPX suppresses the expression of several key subunits of mitochondrial enzyme complex, thus leading to the disruption of mitochondrial oxidative phosphorylation (OXPHOS) in GBM cells. In combination with BTZ, CPX promotes apoptosis in GBM cells through the induction of reactive oxygen species (ROS)-mediated c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) signaling. Moreover, CPX and BTZ synergistically activates nuclear factor kappa B (NF-κB) signaling and induces cellular senescence. Our findings suggest that a combination of CPX and BTZ may serve as a novel therapeutic strategy to enhance the anticancer activity of CPX against GBM. |
url |
https://doi.org/10.1038/s41419-021-03535-9 |
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doaj-a782550ee7604bb88d327a011221ad6e2021-03-11T11:16:31ZengNature Publishing GroupCell Death and Disease2041-48892021-03-0112311310.1038/s41419-021-03535-9Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signalingZhipeng Su0Shengnan Han1Qiumei Jin2Ningning Zhou3Junwan Lu4Fugen Shangguan5Shiyi Yu6Yongzhang Liu7Lu Wang8Jianglong Lu9Qun Li10Lin Cai11Chengde Wang12Xiaohe Tian13Lingyan Chen14Weiming Zheng15Bin Lu16Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical UniversityProtein Quality Control and Diseases Laboratory, Key Laboratory of Medical Genetics of Zhejiang Province, Key Laboratory of Laboratory Medicine, Ministry of Education of China School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityProtein Quality Control and Diseases Laboratory, Key Laboratory of Medical Genetics of Zhejiang Province, Key Laboratory of Laboratory Medicine, Ministry of Education of China School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityProtein Quality Control and Diseases Laboratory, Key Laboratory of Medical Genetics of Zhejiang Province, Key Laboratory of Laboratory Medicine, Ministry of Education of China School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityProtein Quality Control and Diseases Laboratory, Key Laboratory of Medical Genetics of Zhejiang Province, Key Laboratory of Laboratory Medicine, Ministry of Education of China School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityProtein Quality Control and Diseases Laboratory, Key Laboratory of Medical Genetics of Zhejiang Province, Key Laboratory of Laboratory Medicine, Ministry of Education of China School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityProtein Quality Control and Diseases Laboratory, Key Laboratory of Medical Genetics of Zhejiang Province, Key Laboratory of Laboratory Medicine, Ministry of Education of China School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityProtein Quality Control and Diseases Laboratory, Key Laboratory of Medical Genetics of Zhejiang Province, Key Laboratory of Laboratory Medicine, Ministry of Education of China School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityProtein Quality Control and Diseases Laboratory, Key Laboratory of Medical Genetics of Zhejiang Province, Key Laboratory of Laboratory Medicine, Ministry of Education of China School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical UniversityHuaxi MR Research Center (HMRRC), Department of Radiology, Functional and molecular imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan UniversityProtein Quality Control and Diseases Laboratory, Key Laboratory of Medical Genetics of Zhejiang Province, Key Laboratory of Laboratory Medicine, Ministry of Education of China School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityDepartment of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical UniversityProtein Quality Control and Diseases Laboratory, Key Laboratory of Medical Genetics of Zhejiang Province, Key Laboratory of Laboratory Medicine, Ministry of Education of China School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityAbstract Ciclopirox (CPX) is an antifungal drug that has recently been reported to act as a potential anticancer drug. However, the effects and underlying molecular mechanisms of CPX on glioblastoma multiforme (GBM) remain unknown. Bortezomib (BTZ) is the first proteasome inhibitor-based anticancer drug approved to treat multiple myeloma and mantle cell lymphoma, as BTZ exhibits toxic effects on diverse tumor cells. Herein, we show that CPX displays strong anti-tumorigenic activity on GBM. Mechanistically, CPX inhibits GBM cellular migration and invasion by reducing N-Cadherin, MMP9 and Snail expression. Further analysis revealed that CPX suppresses the expression of several key subunits of mitochondrial enzyme complex, thus leading to the disruption of mitochondrial oxidative phosphorylation (OXPHOS) in GBM cells. In combination with BTZ, CPX promotes apoptosis in GBM cells through the induction of reactive oxygen species (ROS)-mediated c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) signaling. Moreover, CPX and BTZ synergistically activates nuclear factor kappa B (NF-κB) signaling and induces cellular senescence. Our findings suggest that a combination of CPX and BTZ may serve as a novel therapeutic strategy to enhance the anticancer activity of CPX against GBM.https://doi.org/10.1038/s41419-021-03535-9 |