MLN4924, a protein neddylation inhibitor, suppresses the growth of human chondrosarcoma through inhibiting cell proliferation and inducing endoplasmic reticulum stress-related apoptosis

Meng Huang Wu, Ching Yu Lee, Tsung Jen Huang, Kuo Yuan Huang, Chih Hsin Tang, Shing Hwa Liu, Kuan Lin Kuo, Feng Che Kuan, Wei Chou Lin, Chung Sheng Shi

研究成果: 雜誌貢獻文章

2 引文 (Scopus)

摘要

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.

原文英語
文章編號72
期刊International Journal of Molecular Sciences
20
發行號1
DOIs
出版狀態已發佈 - 一月 1 2019

指紋

endoplasmic reticulum
Growth Inhibitors
Chondrosarcoma
Endoplasmic Reticulum Stress
Cell proliferation
apoptosis
Cell death
inhibitors
Cells
Cell Proliferation
Apoptosis
proteins
Proteins
Tumors
phosphorylation
Phosphorylation
tumors
Endoplasmic Reticulum
Cytotoxicity
cultured cells

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

引用此文

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.

於: International Journal of Molecular Sciences, 卷 20, 編號 1, 72, 01.01.2019.

研究成果: 雜誌貢獻文章

@article{06c766f156034e1ca254df558f93976b,
title = "MLN4924, a protein neddylation inhibitor, suppresses the growth of human chondrosarcoma through inhibiting cell proliferation and inducing endoplasmic reticulum stress-related apoptosis",
abstract = "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.",
keywords = "Chondrosarcoma, Endoplasmic reticulum stress, MLN4924, NEDD8, Neddylation, Ubiquitin-proteasome system",
author = "Wu, {Meng Huang} and Lee, {Ching Yu} and Huang, {Tsung Jen} and Huang, {Kuo Yuan} and Tang, {Chih Hsin} and Liu, {Shing Hwa} and Kuo, {Kuan Lin} and Kuan, {Feng Che} and Lin, {Wei Chou} and Shi, {Chung Sheng}",
year = "2019",
month = "1",
day = "1",
doi = "10.3390/ijms20010072",
language = "English",
volume = "20",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "MDPI AG",
number = "1",

}

TY - JOUR

T1 - MLN4924, a protein neddylation inhibitor, suppresses the growth of human chondrosarcoma through inhibiting cell proliferation and inducing endoplasmic reticulum stress-related apoptosis

AU - Wu, Meng Huang

AU - Lee, Ching Yu

AU - Huang, Tsung Jen

AU - Huang, Kuo Yuan

AU - Tang, Chih Hsin

AU - Liu, Shing Hwa

AU - Kuo, Kuan Lin

AU - Kuan, Feng Che

AU - Lin, Wei Chou

AU - Shi, Chung Sheng

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Chondrosarcoma

KW - Endoplasmic reticulum stress

KW - MLN4924

KW - NEDD8

KW - Neddylation

KW - Ubiquitin-proteasome system

UR - http://www.scopus.com/inward/record.url?scp=85059228965&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059228965&partnerID=8YFLogxK

U2 - 10.3390/ijms20010072

DO - 10.3390/ijms20010072

M3 - Article

C2 - 30586948

AN - SCOPUS:85059228965

VL - 20

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 1

M1 - 72

ER -