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J Exp Clin Cancer Res. 2019 Nov 4;38(1):448. doi: 10.1186/s13046-019-1467-6.

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

Author information

1
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, Nankai District, Tianjin, 300193, China.
2
School of Pharmaceutical Sciences, Key Laboratory of State Ministry of Education, Key Laboratory of Henan province for Drug Quality Control and Evaluation, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan, China.
3
Kidney Transplantation, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Erqi District, Zhengzhou, 450001, Henan, China.
4
Department of Marine Life Sciences, Jeju National University, Jeju, 63243, Republic of Korea.
5
Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan, 47227, Republic of Korea.
6
School of Pharmaceutical Sciences, Key Laboratory of State Ministry of Education, Key Laboratory of Henan province for Drug Quality Control and Evaluation, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan, China. barton118@163.com.
7
School of Pharmaceutical Sciences, Key Laboratory of State Ministry of Education, Key Laboratory of Henan province for Drug Quality Control and Evaluation, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan, China. cyjin@zzu.edu.cn.

Abstract

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.

KEYWORDS:

Apoptosis; Autophagy; Bladder cancer; C-2; SP600125; SQSTM1/p62

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