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Cellular Oncology
Published in: Cellular Oncology 4/2022

23-07-2022 | Gallbladder Cancer | Original Article

Novel protein kinase inhibitor TT-00420 inhibits gallbladder cancer by inhibiting JNK/JUN-mediated signaling pathway

Authors: Huijie Miao, Yajun Geng, Yang Li, Shijie Tang, Feiling Feng, Weijian Li, Yongsheng Li, Liguo Liu, Rui Zhang, Shimei Qiu, Ying Wu, Zeyu Wang, Ziyi Wang, Ziyu Shao, Ke Liu, Lu Zou, Mao Yang, Yuhao Zhao, Chen Chen, Zhizhen Li, Dadong Zhang, Peng Peng, Xiaoyan Qiang, Frank Wu, Yongning He, Luonan Chen, Dongxi Xiang, Xiaoqing Jiang, Maolan Li, Yun Liu, Yingbin Liu

Published in: Cellular Oncology | Issue 4/2022

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Abstract

Purpose

This study aimed to investigate the efficiency of our chemically synthesized TT-00420, a novel spectrum-selective multiple protein kinase inhibitor, in cultured cells and animal models of gallbladder cancer (GBC) and explore its potential mechanism.

Methods

Multiple GBC models were established to assess the anti-tumor efficiency, toxicity, and pharmacokinetics of TT-00420. Integrated transcriptomic, proteomic and phosphoproteomic analysis was conducted to identify potential downstream effectors of TT-00420. Western blotting, qRT-PCR, nuclear-cytoplasm separation, and immunofluorescence were performed to confirm the multi-omic results and explore the molecular mechanism of TT-00420. Immunohistochemistry was used to detect FGFR1 and p-FGFR1 expression levels in GBC samples. Autodock software was utilized to investigate the potential binding mode between the TT-00420 and the human FGFR1.

Results

We found that TT-00420 exerted potent growth inhibition of GBC cell lines and multiple xenograft models. Treatment of mice with 15 mg/kg TT-00420 via gavage displayed a half-life of 1.8 h in the blood and rapid distribution to the liver, kidneys, lungs, spleen, and tumors at 0.25 h, but no toxicity to these organs over 2 weeks. Multi-omic analysis revealed c-Jun as a potential downstream effector after TT-00420 treatment. Mechanistically, TT-00420 showed rigorous ability to block FGFR1 and its downstream JNK-JUN (S63/S73) signaling pathway, and induce c-Jun S243-dependent MEK/ERK reactivation, leading to FASLG-dependent tumor cell death. Finally, we found that FGFR1 and p-FGFR1 expression was elevated in GBC patients and these levels correlated with decreased patient survival.

Conclusions

TT-00420 shows potent antitumor efficacy and may serve as a novel agent to improve GBC prognosis.
Appendix
Available only for authorised users
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Metadata
Title
Novel protein kinase inhibitor TT-00420 inhibits gallbladder cancer by inhibiting JNK/JUN-mediated signaling pathway
Authors
Huijie Miao
Yajun Geng
Yang Li
Shijie Tang
Feiling Feng
Weijian Li
Yongsheng Li
Liguo Liu
Rui Zhang
Shimei Qiu
Ying Wu
Zeyu Wang
Ziyi Wang
Ziyu Shao
Ke Liu
Lu Zou
Mao Yang
Yuhao Zhao
Chen Chen
Zhizhen Li
Dadong Zhang
Peng Peng
Xiaoyan Qiang
Frank Wu
Yongning He
Luonan Chen
Dongxi Xiang
Xiaoqing Jiang
Maolan Li
Yun Liu
Yingbin Liu
Publication date
23-07-2022
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 4/2022
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-022-00692-7

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