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MLN4924, a Protein Neddylation Inhibitor, Suppresses the Growth of Human Chondrosarcoma through Inhibiting Cell Proliferation and Inducing Endoplasmic Reticulum Stress-Related Apoptosis

Chondrosarcoma, a heterogeneous malignant bone tumor, commonly produces cartilage matrix, which generally has no response to conventional therapies. Studies have reported that MLN4924, a NEDD8-activating enzyme inhibitor, achieves antitumor effects against numerous malignancies. In this study, the s...

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Autores principales: Wu, Meng-Huang, Lee, Ching-Yu, Huang, Tsung-Jen, Huang, Kuo-Yuan, Tang, Chih-Hsin, Liu, Shing-Hwa, Kuo, Kuan-Lin, Kuan, Feng-Che, Lin, Wei-Chou, Shi, Chung-Sheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337205/
https://www.ncbi.nlm.nih.gov/pubmed/30586948
http://dx.doi.org/10.3390/ijms20010072
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author Wu, Meng-Huang
Lee, Ching-Yu
Huang, Tsung-Jen
Huang, Kuo-Yuan
Tang, Chih-Hsin
Liu, Shing-Hwa
Kuo, Kuan-Lin
Kuan, Feng-Che
Lin, Wei-Chou
Shi, Chung-Sheng
author_facet Wu, Meng-Huang
Lee, Ching-Yu
Huang, Tsung-Jen
Huang, Kuo-Yuan
Tang, Chih-Hsin
Liu, Shing-Hwa
Kuo, Kuan-Lin
Kuan, Feng-Che
Lin, Wei-Chou
Shi, Chung-Sheng
author_sort Wu, Meng-Huang
collection PubMed
description Chondrosarcoma, a heterogeneous malignant bone tumor, commonly produces cartilage matrix, which generally has no response to conventional therapies. Studies have reported that MLN4924, a NEDD8-activating enzyme inhibitor, achieves antitumor effects against numerous malignancies. In this study, the suppressive effects of MLN4924 on human chondrosarcoma cell lines were investigated using in vitro and in vivo assays, which involved measuring cell viability, cytotoxicity, apoptosis, proliferation, cell cycles, molecule-associated cell cycles, apoptosis, endoplasmic reticulum (ER) stress, and tumor growth in a xenograft mouse model. Our results demonstrated that MLN4924 significantly suppressed cell viability, exhibited cytotoxicity, and stimulated apoptosis through the activation of caspase-3 and caspase-7 in chondrosarcoma cell lines. Furthermore, MLN4924 significantly inhibited cell proliferation by diminishing the phosphorylation of histone H3 to cause G2/M cell cycle arrest. In addition, MLN4924 activated ER stress–related apoptosis by upregulating the phosphorylation of c-Jun N-terminal kinase (JNK), enhancing the expression of GRP78 and CCAAT-enhancer-binding protein homologous protein (CHOP, an inducer of endoplasmic ER stress–related apoptosis) and activating the cleavage of caspase-4. Moreover, MLN4924 considerably inhibited the growth of chondrosarcoma tumors in a xenograft mouse model. Finally, MLN4924-mediated antichondrosarcoma properties can be accompanied by the stimulation of ER stress–related apoptosis, implying that targeting neddylation by MLN4924 is a novel therapeutic strategy for treating chondrosarcoma.
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spelling pubmed-63372052019-01-22 MLN4924, a Protein Neddylation Inhibitor, Suppresses the Growth of Human Chondrosarcoma through Inhibiting Cell Proliferation and Inducing Endoplasmic Reticulum Stress-Related Apoptosis Wu, Meng-Huang Lee, Ching-Yu Huang, Tsung-Jen Huang, Kuo-Yuan Tang, Chih-Hsin Liu, Shing-Hwa Kuo, Kuan-Lin Kuan, Feng-Che Lin, Wei-Chou Shi, Chung-Sheng Int J Mol Sci Article Chondrosarcoma, a heterogeneous malignant bone tumor, commonly produces cartilage matrix, which generally has no response to conventional therapies. Studies have reported that MLN4924, a NEDD8-activating enzyme inhibitor, achieves antitumor effects against numerous malignancies. In this study, the suppressive effects of MLN4924 on human chondrosarcoma cell lines were investigated using in vitro and in vivo assays, which involved measuring cell viability, cytotoxicity, apoptosis, proliferation, cell cycles, molecule-associated cell cycles, apoptosis, endoplasmic reticulum (ER) stress, and tumor growth in a xenograft mouse model. Our results demonstrated that MLN4924 significantly suppressed cell viability, exhibited cytotoxicity, and stimulated apoptosis through the activation of caspase-3 and caspase-7 in chondrosarcoma cell lines. Furthermore, MLN4924 significantly inhibited cell proliferation by diminishing the phosphorylation of histone H3 to cause G2/M cell cycle arrest. In addition, MLN4924 activated ER stress–related apoptosis by upregulating the phosphorylation of c-Jun N-terminal kinase (JNK), enhancing the expression of GRP78 and CCAAT-enhancer-binding protein homologous protein (CHOP, an inducer of endoplasmic ER stress–related apoptosis) and activating the cleavage of caspase-4. Moreover, MLN4924 considerably inhibited the growth of chondrosarcoma tumors in a xenograft mouse model. Finally, MLN4924-mediated antichondrosarcoma properties can be accompanied by the stimulation of ER stress–related apoptosis, implying that targeting neddylation by MLN4924 is a novel therapeutic strategy for treating chondrosarcoma. MDPI 2018-12-24 /pmc/articles/PMC6337205/ /pubmed/30586948 http://dx.doi.org/10.3390/ijms20010072 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wu, Meng-Huang
Lee, Ching-Yu
Huang, Tsung-Jen
Huang, Kuo-Yuan
Tang, Chih-Hsin
Liu, Shing-Hwa
Kuo, Kuan-Lin
Kuan, Feng-Che
Lin, Wei-Chou
Shi, Chung-Sheng
MLN4924, a Protein Neddylation Inhibitor, Suppresses the Growth of Human Chondrosarcoma through Inhibiting Cell Proliferation and Inducing Endoplasmic Reticulum Stress-Related Apoptosis
title MLN4924, a Protein Neddylation Inhibitor, Suppresses the Growth of Human Chondrosarcoma through Inhibiting Cell Proliferation and Inducing Endoplasmic Reticulum Stress-Related Apoptosis
title_full MLN4924, a Protein Neddylation Inhibitor, Suppresses the Growth of Human Chondrosarcoma through Inhibiting Cell Proliferation and Inducing Endoplasmic Reticulum Stress-Related Apoptosis
title_fullStr MLN4924, a Protein Neddylation Inhibitor, Suppresses the Growth of Human Chondrosarcoma through Inhibiting Cell Proliferation and Inducing Endoplasmic Reticulum Stress-Related Apoptosis
title_full_unstemmed MLN4924, a Protein Neddylation Inhibitor, Suppresses the Growth of Human Chondrosarcoma through Inhibiting Cell Proliferation and Inducing Endoplasmic Reticulum Stress-Related Apoptosis
title_short MLN4924, a Protein Neddylation Inhibitor, Suppresses the Growth of Human Chondrosarcoma through Inhibiting Cell Proliferation and Inducing Endoplasmic Reticulum Stress-Related Apoptosis
title_sort mln4924, a protein neddylation inhibitor, suppresses the growth of human chondrosarcoma through inhibiting cell proliferation and inducing endoplasmic reticulum stress-related apoptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337205/
https://www.ncbi.nlm.nih.gov/pubmed/30586948
http://dx.doi.org/10.3390/ijms20010072
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