Abstract

BackgroundLicorice is an herb extensively used for both culinary and medicinal purposes. Various constituents of licorice have been shown to exhibit anti-tumorigenic effect in diverse cancer types. However, majority of these studies focus on the aspect of their growth-suppressive role. In this study, we systematically analyzed known licorice’s constituents on the goal of identifying component(s) that can effectively suppress both cell migration and growth.MethodsEffect of licorice’s constituents on cell growth was evaluated by MTT assay while cell migration was assessed by both wound-healing and Transwell assays. Cytoskeleton reorganization and focal adhesion assembly were visualized by immunofluorescence staining with labeled phalloidin and anti-paxillin antibody. Activity of Src in cells was judged by western blot using phosphor-Src416 antibody while Src kinase activity was measured using Promega Src kinase assay system. Anti-tumorigenic capabilities of isoliquiritigenin (ISL) and 2, 4, 2′, 4’-Tetrahydroxychalcone (THC) were investigated using lung cancer xenograft model.ResultsUsing a panel of lung cancer cell lines, ISL was identified as the only licorice’s constituent capable of inhibiting both cell migration and growth. ISL-led inhibition in cell migration resulted from impaired cytoskeleton reorganization and focal adhesion assembly. Assessing the phosphorylation of 141 cytoskeleton dynamics-associated proteins revealed that ISL reduced the abundance of Tyr421-phosphorylation of cortactin, Tyr925- and Tyr861-phosphorylation of FAK, indicating the involvement of Src because these sites are known to be phosphorylated by Src. Enigmatically, ISL inhibited Src in cells while displayed no effect on Src activity in cell-free system. The discrepancy was explained by the observation that THC, one of the major ISL metabolite identified in lung cancer cells abrogated Src activity both in cells and cell-free system. Similar to ISL, THC deterred cell migration and abolished cytoskeleton reorganization/focal adhesion assembly. Furthermore, we showed both ISL and THC suppressed in vitro lung cancer cell invasion and in vivo tumor progression.ConclusionOur study suggests that ISL inhibits lung cancer cell migration and tumorigenesis by interfering with Src through its metabolite THC. As licorice is safely used for culinary purposes, our study suggests that ISL or THC may be safely used as a Src inhibitor.

Highlights

  • Licorice is an herb extensively used for both culinary and medicinal purposes

  • We showed that ISL was the only compound effectively inhibiting cell migration and its motility-inhibitory effect was through its ability to impair cytoskeleton reorganization and focal adhesion assembly

  • ISL effectively inhibits non-small cell lung carcinomas (NSCLC) cell migration To investigate the potency of components in licorice to suppress cell migration, we first performed Transwell and wound-healing assays to evaluate migratory potential on a panel of NSCLC cell lines and observed that H1299, A549, H1975 and H2228 cells were highly migratory while others were either little or poorly migratory (Additional file 1: Figure S1A and B)

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Summary

Introduction

Various constituents of licorice have been shown to exhibit anti-tumorigenic effect in diverse cancer types. Majority of these studies focus on the aspect of their growth-suppressive role. Isoliquiritigenin (ISL), one of the flavonoids in licorice, can inhibit growth of diverse cancer types including breast, lung, cervical, ovary, prostate and colon cancer by inducing apoptosis, autophagy and causing DNA damage [1,2,3,4,5,6]. ISL has been shown to exhibit inhibitory effect on migration of breast and prostate cancer cells [7,8,9]. Anti-tumorigenic effect of ISL has been associated with the interference of various signaling pathways including JNK/AP1, PI3K/Akt and VEGF/VEGF2 [8, 14, 15], direct target of ISL remains to be characterized

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