Fibroblast growth factor receptor (FGFR) 2 and its downstream signaling cascades, PI3 K/AKT/mTOR is playing an important role in cell survival and proliferations. In this study, we firstly found that picrasidine Q (PQ), an alkaloid component extracted from Angelica keiskei species, has the capacity of anti-cell transformation and anti-cancer. After ligand shape similarity approach of PQ, we found that PQ targeted FGFR 2 and verified by FGFR2 kinase assay as well as computational docking model. FGFR2 highly expressed in esophageal cancer tissues and PQ inhibited fibroblast growth factor (FGF)-induced cell transformation. Furthermore, PQ inhibited cell proliferation and induced cell cycle arrest and apoptosis in KYSE30, KYSE410, and KYSE450 esophageal squamous cell carcinoma (ESCC) cells. It was confirmed by detecting of biological markers such as cyclinD1, cyclinD3 and cyclinB1 for cell cycle or cleaved caspase-7, caspase-3, and PARP for apoptosis. PQ targeting of FGFR2 kinase activities suppressed downstream target proteins including phosphorylation of AKT and mTOR but not MEK/ERK signaling pathways. Taken together, our results are the first to identify that PQ might be a chemopreventive and chemotherapeutic agent by direct targeting FGFR2 and inhibiting cell proliferation of ESCC cells.
Bibliographical noteFunding Information:
National Natural Science Foundation of China/Foreign Young Scientist, Grant number: NSFC 81650110530; National Natural Science Foundation of China, Grant number: NSFC81672767; National Institutes of Health, Grant numbers: CA187027, CA196639, CA166011
This work was supported by National Institutes of Health, USA, CA187027, CA196639, CA166011 and Key program of Henan Province, China, Grant NO.161100510300 (Z.G. Dong), and National Natural Science Foundation of China NSFC81672767 (M.H.Lee) and Foreign Young Scientist NSFC 81650110530 (M. Fredimoses), Zhengzhou Intellectual Property Office and Henan Provincial Government, China. Funders had no role in producing this manuscript. We wish to thank Ran Yang in China-US (Henan) Hormel Cancer Institute for supporting experiments.
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Copyright 2018 Elsevier B.V., All rights reserved.
- AKT/mTOR signaling pathways
- esophageal squamous cell carcinoma
- picrasidine Q (PQ)