Cargando…
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...
Autores principales: | , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783465677695221760 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6829950 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT yuhaiyang sp600125enhancesc2inducedcelldeathbytheswitchfromautophagytoapoptosisinbladdercancercells AT wuchunli sp600125enhancesc2inducedcelldeathbytheswitchfromautophagytoapoptosisinbladdercancercells AT wangxiangyu sp600125enhancesc2inducedcelldeathbytheswitchfromautophagytoapoptosisinbladdercancercells AT banqianhong sp600125enhancesc2inducedcelldeathbytheswitchfromautophagytoapoptosisinbladdercancercells AT quanchunhua sp600125enhancesc2inducedcelldeathbytheswitchfromautophagytoapoptosisinbladdercancercells AT liumengbo sp600125enhancesc2inducedcelldeathbytheswitchfromautophagytoapoptosisinbladdercancercells AT donghangqi sp600125enhancesc2inducedcelldeathbytheswitchfromautophagytoapoptosisinbladdercancercells AT lijinfeng sp600125enhancesc2inducedcelldeathbytheswitchfromautophagytoapoptosisinbladdercancercells AT kimgiyoung sp600125enhancesc2inducedcelldeathbytheswitchfromautophagytoapoptosisinbladdercancercells AT choiyunghyun sp600125enhancesc2inducedcelldeathbytheswitchfromautophagytoapoptosisinbladdercancercells AT wangzhenya sp600125enhancesc2inducedcelldeathbytheswitchfromautophagytoapoptosisinbladdercancercells AT jinchengyun sp600125enhancesc2inducedcelldeathbytheswitchfromautophagytoapoptosisinbladdercancercells |