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SP600125 enhances C-2-induced cell death by the switch from autophagy to apoptosis in bladder cancer cells

BACKGROUND: A natural compound Jaspine B and its derivative possess potential anti-cancer activities; However, little is known about the underlying mechanism. Here, the role of a new autophagy inducer Jaspine B derivative C-2 in suppressing bladder cancer cells was researched in vitro and in vivo. M...

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Autores principales: Yu, Haiyang, Wu, Chun-Li, Wang, Xiangyu, Ban, Qianhong, Quan, Chunhua, Liu, Mengbo, Dong, Hangqi, Li, Jinfeng, Kim, Gi-Young, Choi, Yung Hyun, Wang, Zhenya, Jin, Cheng-Yun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829950/
https://www.ncbi.nlm.nih.gov/pubmed/31685029
http://dx.doi.org/10.1186/s13046-019-1467-6
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author Yu, Haiyang
Wu, Chun-Li
Wang, Xiangyu
Ban, Qianhong
Quan, Chunhua
Liu, Mengbo
Dong, Hangqi
Li, Jinfeng
Kim, Gi-Young
Choi, Yung Hyun
Wang, Zhenya
Jin, Cheng-Yun
author_facet Yu, Haiyang
Wu, Chun-Li
Wang, Xiangyu
Ban, Qianhong
Quan, Chunhua
Liu, Mengbo
Dong, Hangqi
Li, Jinfeng
Kim, Gi-Young
Choi, Yung Hyun
Wang, Zhenya
Jin, Cheng-Yun
author_sort Yu, Haiyang
collection PubMed
description BACKGROUND: A natural compound Jaspine B and its derivative possess potential anti-cancer activities; However, little is known about the underlying mechanism. Here, the role of a new autophagy inducer Jaspine B derivative C-2 in suppressing bladder cancer cells was researched in vitro and in vivo. METHODS: The underlying mechanisms and anticancer effect of C-2 in bladder cancer cells were investigated by MTT, western blotting, immunoprecipitation and immunofluorescence assays. The key signaling components were investigated by using pharmacological inhibitors or specific siRNAs. In vivo, we designed a C-2 and SP600125 combination experiment to verify the effectiveness of compound. RESULTS: C-2 exhibits cytotoxic effect on bladder cancer cells, and JNK activated by C-2 triggers autophagy and up-regulates SQSTM1/p62 proteins, contributing to activation of Nrf2 pathway. Utilization of JNK inhibitor SP600125 or knockdown of JNK by siRNA potentiate the cytotoxicity of C-2 through down-regulation of p62 and LC3II proteins and up-regulation of active-Caspase3 proteins, enhance the cell death effect, facilitating the switch from autophagy to apoptosis. In vivo study, C-2 suppresses tumor growth in a xenograft mouse model of EJ cells without observed toxicity. Combined treatment with SP600125 further enhances tumor inhibition of C-2 associated with enhanced activation of caspase3 and reduction of autophagy. CONCLUSIONS: It reveals a series of molecular mechanisms about SP600125 potentiate the cytotoxicity and tumor inhibition of C-2 in bladder cancer cells through promoting C-2-induced apoptosis, expecting it provides research basis and theoretical support for new drugs development.
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spelling pubmed-68299502019-11-07 SP600125 enhances C-2-induced cell death by the switch from autophagy to apoptosis in bladder cancer cells Yu, Haiyang Wu, Chun-Li Wang, Xiangyu Ban, Qianhong Quan, Chunhua Liu, Mengbo Dong, Hangqi Li, Jinfeng Kim, Gi-Young Choi, Yung Hyun Wang, Zhenya Jin, Cheng-Yun J Exp Clin Cancer Res Research BACKGROUND: A natural compound Jaspine B and its derivative possess potential anti-cancer activities; However, little is known about the underlying mechanism. Here, the role of a new autophagy inducer Jaspine B derivative C-2 in suppressing bladder cancer cells was researched in vitro and in vivo. METHODS: The underlying mechanisms and anticancer effect of C-2 in bladder cancer cells were investigated by MTT, western blotting, immunoprecipitation and immunofluorescence assays. The key signaling components were investigated by using pharmacological inhibitors or specific siRNAs. In vivo, we designed a C-2 and SP600125 combination experiment to verify the effectiveness of compound. RESULTS: C-2 exhibits cytotoxic effect on bladder cancer cells, and JNK activated by C-2 triggers autophagy and up-regulates SQSTM1/p62 proteins, contributing to activation of Nrf2 pathway. Utilization of JNK inhibitor SP600125 or knockdown of JNK by siRNA potentiate the cytotoxicity of C-2 through down-regulation of p62 and LC3II proteins and up-regulation of active-Caspase3 proteins, enhance the cell death effect, facilitating the switch from autophagy to apoptosis. In vivo study, C-2 suppresses tumor growth in a xenograft mouse model of EJ cells without observed toxicity. Combined treatment with SP600125 further enhances tumor inhibition of C-2 associated with enhanced activation of caspase3 and reduction of autophagy. CONCLUSIONS: It reveals a series of molecular mechanisms about SP600125 potentiate the cytotoxicity and tumor inhibition of C-2 in bladder cancer cells through promoting C-2-induced apoptosis, expecting it provides research basis and theoretical support for new drugs development. BioMed Central 2019-11-04 /pmc/articles/PMC6829950/ /pubmed/31685029 http://dx.doi.org/10.1186/s13046-019-1467-6 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Yu, Haiyang
Wu, Chun-Li
Wang, Xiangyu
Ban, Qianhong
Quan, Chunhua
Liu, Mengbo
Dong, Hangqi
Li, Jinfeng
Kim, Gi-Young
Choi, Yung Hyun
Wang, Zhenya
Jin, Cheng-Yun
SP600125 enhances C-2-induced cell death by the switch from autophagy to apoptosis in bladder cancer cells
title SP600125 enhances C-2-induced cell death by the switch from autophagy to apoptosis in bladder cancer cells
title_full SP600125 enhances C-2-induced cell death by the switch from autophagy to apoptosis in bladder cancer cells
title_fullStr SP600125 enhances C-2-induced cell death by the switch from autophagy to apoptosis in bladder cancer cells
title_full_unstemmed SP600125 enhances C-2-induced cell death by the switch from autophagy to apoptosis in bladder cancer cells
title_short SP600125 enhances C-2-induced cell death by the switch from autophagy to apoptosis in bladder cancer cells
title_sort sp600125 enhances c-2-induced cell death by the switch from autophagy to apoptosis in bladder cancer cells
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829950/
https://www.ncbi.nlm.nih.gov/pubmed/31685029
http://dx.doi.org/10.1186/s13046-019-1467-6
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