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Verticillin A suppresses HGF-induced migration and invasion via repression of the c-Met/FAK/Src pathway in human gastric and cervical cancer cells

Authors Lu J, Li X, Tu K, Guan Y, Fung KP, Liu F

Received 14 March 2019

Accepted for publication 12 June 2019

Published 26 July 2019 Volume 2019:12 Pages 5823—5833


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Carlos E Vigil

Jingxin Lu,*,1,2 Xia Li,*,2,3 Kai Tu,1,2 Yuelin Guan,1,2 Kwok-Pui Fung,2,4 Feiyan Liu1,2

1Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou 310058, People’s Republic of China; 2Joint Centre of Zhejiang University and the Chinese University of Hong Kong on Natural Products and Toxicology Research, Zhejiang University, Hangzhou, People’s Republic of China; 3Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou 310022, People’s Republic of China; 4School of Biomedical Sciences (SBS), The Chinese University of Hong Kong, Shatin, Hong Kong SAR, People’s Republic of China

*These authors contributed equally to this work

Background and purpose: Verticillin A is a fungal epipolythiodioxopiperazine (ETP) metabolite that was isolated from Amanita flavorubescens Alk infected by Verticillium sp. It was previously proven to possess potent anti-tumor cell growth activity, and we have recently determined that verticillin A is a selective inhibitor of H3K9me3-specific histone methyltransferase. The objective of this study was to find out whether verticillin A is an effective agent for suppression of gastric and cervical tumor progression.
Materials and methods: Wound healing and transwell assays was performed to evaluate the effect of verticillin A on hepatocyte growth factor (HGF)-induced AGS and HeLa cells migration and invasion in vitro. Western blot was used to detect signaling proteins verticillin A affected.
Results: We determined that verticillin A effectively suppressed hepatocyte growth factor (HGF)-induced AGS and HeLa cells migration and invasion in vitro. At the molecular level, we demonstrated that verticillin A inhibited HGF-induced c-Met phosphorylation and repressed the expression of total c-Met protein in AGS and HeLa cells, resulting from reduced expression of fatty acid synthase. In addition, verticillin A could suppress c-Met downstream FAK/Src signaling pathways by impairing c-Met phosphorylation induced by HGF.
Conclusion: Our study demonstrated verticillin A inhibits the migration ability of human gastric cancer (AGS) cells and cervical cancer (HeLa) cells by targeting c-Met and its downstream FAK/Src signaling pathways, and suggested that verticillin A acts as a novel HGF/c-Met inhibitor by reducing expression of this receptor.

Keywords: verticillin A, gastric and cervical cancers, cell migration, c-Met, FAK

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