Yanan Liu1, Liting Zhang1, Xiaolu Chen1, Daoxing Chen1, Xueqin Shi1, Jiali Song1, Jianzhang Wu1, Fengyu Huang1, Qinqin Xia1, Youqun Xiang2, Xiaohui Zheng3, Yuepiao Cai4. 1. School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China. 2. Department of Colon and Rectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. tom502@sina.com. 3. School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China. zhengxh@wmu.edu.cn. 4. School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, Zhejiang, China. ypcai@wmu.edu.cn.
Abstract
BACKGROUND: Fibroblast growth factor receptor (FGFR) signaling influenced tumour occurrence and development. Overexpression of FGFR had been observed in many types of cancers, including colon cancer. FGFR inhibitor is considered to be effective in treating colon cancer patients. METHODS: First, the kinase inhibition rate was determined. MTT, western blotting, colony formation, EdU and comet assays were performed to evaluate the anti-tumour effects of F1-7 in vitro. RNA-seq and bioinformatics analysis were used for further verification. Additionally, a xenograft model was generated to investigate the anti-tumour effect of F1-7. RESULTS: F1-7 can inhibit the proliferation of colon cancer cells in vitro. It could significantly inhibit FGFR phosphorylation and its downstream signaling pathway. Whole-genome RNA-seq analysis found that the changed genes were not only functionally focused on MAPK signaling pathway but also related to cell apoptosis and ferroptosis. Experimental evidence demonstrated that F1-7 can directly increase the level of cellular DNA damage. The occurrence of DNA damage led to cell cycle arrest and inhibition of cell metastasis and cell apoptosis. Mouse model experiments also confirmed that F1-7 could inhibit tumour growth by inhibiting the FGFR pathway. CONCLUSIONS: F1-7 exhibits anti-tumour activity by inhibiting the FGFR pathway. It could be a novel therapeutic agent for targeting colon cancer cells.
BACKGROUND: Fibroblast growth factor receptor (FGFR) signaling influenced tumour occurrence and development. Overexpression of FGFR had been observed in many types of cancers, including colon cancer. FGFR inhibitor is considered to be effective in treating colon cancer patients. METHODS: First, the kinase inhibition rate was determined. MTT, western blotting, colony formation, EdU and comet assays were performed to evaluate the anti-tumour effects of F1-7 in vitro. RNA-seq and bioinformatics analysis were used for further verification. Additionally, a xenograft model was generated to investigate the anti-tumour effect of F1-7. RESULTS: F1-7 can inhibit the proliferation of colon cancer cells in vitro. It could significantly inhibit FGFR phosphorylation and its downstream signaling pathway. Whole-genome RNA-seq analysis found that the changed genes were not only functionally focused on MAPK signaling pathway but also related to cell apoptosis and ferroptosis. Experimental evidence demonstrated that F1-7 can directly increase the level of cellular DNA damage. The occurrence of DNA damage led to cell cycle arrest and inhibition of cell metastasis and cell apoptosis. Mouse model experiments also confirmed that F1-7 could inhibit tumour growth by inhibiting the FGFR pathway. CONCLUSIONS: F1-7 exhibits anti-tumour activity by inhibiting the FGFR pathway. It could be a novel therapeutic agent for targeting colon cancer cells.
Authors: Christian von Mering; Martijn Huynen; Daniel Jaeggi; Steffen Schmidt; Peer Bork; Berend Snel Journal: Nucleic Acids Res Date: 2003-01-01 Impact factor: 16.971