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A novel chalcone derivative suppresses melanoma cell growth through targeting Fyn/Stat3 pathway.

Abstract：

Background:Fyn has been documented to have oncogenic features in multiple tumors, which might be a potential therapeutic target, however, few studies on the function role of Fyn and its specific inhibitors in melanoma. Methods:We investigated the impacts of Fyn and its inhibitor Lj-1-60 on melanoma through bioinformatics analysis, western blot, cell viability, cell cycle and apoptosis and xenograft tumor model as well as immunohistochemical staining. Pull-down and in vitro kinase assay were used to demonstrate Lj-1-60 targeting Fyn. Transcriptome sequencing and RT-PCR were adopted to confirm the potential mechanisms of Lj-1-60 in melanoma. Results:Our findings showed that Fyn was overexpressed in melanoma cells and knocked down of Fyn suppressed the proliferation of melanoma cells. To identify the potential inhibitors of Fyn, our in-house library including total of 111,277 chemicals was conducted to vitro screening, among those compounds, 83 inhibitors were further detected to explore the effect on melanoma cells growth and discovered a novel chalcone derivative Lj-1-60 that exhibited low cellular toxicity and high anti-tumor efficacy. Lj-1-60 directly was associated with Fyn and inhibited the Fyn kinase activity with Stat3 as substrate. What's more, Lj-1-60 suppressed the proliferation of melanoma in vitro and in vivo through inducing cell cycle arrest and apoptosis. Moreover, the activation of Stat3 had also been abrogated both in Lj-1-60 treated melanoma cells or Fyn knocked down cells. Conclusion:Our study revealed a novel Fyn inhibitor that could significantly suppress melanoma growth, which is a promising potential inhibitor for melanoma treatment.

journal_name

Cancer Cell Int

journal_title

Cancer cell international

authors

Tang L,Long J,Li K,Zhang X,Chen X,Peng C

doi

10.1186/s12935-020-01336-2

subject

Has Abstract

pub_date

2020-06-18 00:00:00

pages

256

issn

1475-2867

pii

1336

journal_volume

20

pub_type

杂志文章

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