SP600125 enhances C-2-induced cell death by the switch from autophagy to apoptosis in bladder cancer cells
| Autor: | Yung Hyun Choi, Mengbo Liu, Chunhua Quan, Haiyang Yu, Hangqi Dong, Zhenya Wang, Chun-Li Wu, Qianhong Ban, Jinfeng Li, Gi-Young Kim, Xiangyu Wang, Cheng-Yun Jin |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Small interfering RNA Programmed cell death Cell Survival MAP Kinase Kinase 4 SQSTM1/p62 Apoptosis lcsh:RC254-282 Mice 03 medical and health sciences 0302 clinical medicine Sphingosine In vivo Cell Line Tumor Sequestosome-1 Protein Autophagy medicine Animals Humans Cytotoxic T cell C-2 Cytotoxicity Cell Proliferation Anthracenes SP600125 Bladder cancer Caspase 3 Chemistry Research Drug Synergism lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Xenograft Model Antitumor Assays Treatment Outcome 030104 developmental biology Urinary Bladder Neoplasms Oncology 030220 oncology & carcinogenesis Cancer research |
| Zdroj: | Journal of Experimental & Clinical Cancer Research, Vol 38, Iss 1, Pp 1-13 (2019) Journal of Experimental & Clinical Cancer Research : CR |
| ISSN: | 1756-9966 |
| DOI: | 10.1186/s13046-019-1467-6 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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