Suppression of lung cancer progression by isoliquiritigenin through its metabolite 2, 4, 2’, 4’-Tetrahydroxychalcone

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.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0902-4) contains supplementary material, which is available to authorized users.

Dietary Compound Isoliquiritigenin, an Antioxidant from Licorice, Suppresses Triple-Negative Breast Tumor Growth via Apoptotic Death Program Activation in Cell and Xenograft Animal Models

“…ISL has also been reported to exert potential antitumor activity on multistage carcinogenesis procession in cervical [19], ovarian [20], prostate [21], and lung cancers [22]. Previously, we found that ISL of 10 µM exhibits an inhibitory effect on Vascular endothelial growth factor (VEGF)-induced triple-negative breast cancer migration and invasion through downregulation of the PI3K-AKT-MAPK signaling pathway [23].…”

Isoliquiritigenin Inhibits Ovarian Cancer Metastasis by Reversing Epithelial-to-Mesenchymal Transition

“…We posit that effective anti-ovarian cancer therapeutic approaches can be established by deterring EMT in ovarian cancer. We have previously shown that ISL, a flavonoid compound, is a potent Src inhibitor [29], and the Src signaling pathway is critical for the maintenance of EMT traits in ovarian cancer cells [33]. This raises the possibility that ISL may possess the capacity to block ovarian cancer EMT and subsequent peritoneal metastasis.…”

“…ISL has also been shown to inhibit breast and lung cancer cell migration [26,27,28]. We previously showed that ISL strongly deterred lung cancer cell migration and tumorigenicities by interfering with the Src signaling pathway through its metabolite tetrahydroxychalcone (THC) [29]. In several recent reports, ISL was found to block cell growth through the induction of apoptosis and autophagy in ovarian cancer cells [30,31].…”

ERBB3-induced furin promotes the progression and metastasis of ovarian cancer via the IGF1R/STAT3 signaling axis

“…The in vitro invasion assay was performed using Matrigel invasion chambers (BD Biosciences, Bedford, MA, USA) as previously described ( 39 ). Briefly, 1×10 5 serum starved cells were plated into each invasion into each upper chamber, and medium containing 10% fetal calf serum was added to the lower chambers.…”