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

• Published in: Journal of experimental & clinical cancer research 2019-11, Vol.38 (1), p.448-13, Article 448
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Anthracenes - administration & dosage; Anthracenes - pharmacology; Apoptosis; Autophagy; Autophagy - drug effects; Biochemistry; Bladder cancer; C-2; Cancer; Cancer cells; Care and treatment; Caspase 3 - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Drug Synergism; Humans; Investigations; MAP Kinase Kinase 4; Mice; Oncology, Experimental; Proteins; Sequestosome-1 Protein - metabolism; SP600125; Sphingosine - analogs & derivatives; SQSTM1/p62; Treatment Outcome; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-019-1467-6

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. 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. 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. 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.