Isoliquiritigenin Suppressed Esophageal Squamous Carcinoma Growth by Blocking EGFR Activation and Inducing Cell Cycle Arrest

Abstract

Isoliquiritigenin (ILQ) is a natural product isolated from licorice root which has served as traditional Chinese medicine for a long time. Recently, the antitumor effects of ILQ have been widely studied in various cancers, but the role and related mechanisms of ILQ in esophageal squamous carcinoma cells (ESCC) are still poorly understood. In our studies, ILQ showed profound antitumor activities in ESCC cells. In vitro, ILQ substantially inhibited cell proliferation and anchorage-independent growth in a panel of human ESCC cells. Mechanism studies showed that EGFR signaling pathway played an important role for ILQ to exert its antitumor activity in ESCC. Exposure to isoliquiritigenin substantially decreased EGF-induced EGFR activation and its downstream Akt and ERK1/2 signaling pathway. EGFR knockdown with shRNA in ESCC cell significantly reduced the sensitivity of cancer cells to ILQ. Moreover, it was found that ILQ had a significantly inhibitory effect on AP-1 family, the protein of Jun and Fos subfamilies was substantially downregulated, and the transcriptional activity of AP-1 family was dramatically suppressed by ILQ. By reducing the expression of cyclin D1, ESCC cells were induced G0/G1 arrest, and cell division was substantially blocked. Finally, the antitumor potency of ILQ was validated in xenograft models and the tumor growth was prominently restrained by ILQ. Briefly, our study showed that ILQ, or its analogue, appeared to be a promising new therapeutic agent for ESCC management.

Homeobox A7 promotes esophageal squamous cell carcinoma progression through C‐C motif chemokine ligand 2‐mediated tumor‐associated macrophage recruitment

“…Intracellular signaling plays predominant roles in regulating tumor malignant features 37 . In ESCC, EGF‐induced activation of PI3K/AKT and ERK1/2 pathways was well elucidated 38,39 . Our results are consistent with the findings of previous studies, demonstrating that these intercellular signaling pathways were under the regulation of HOXA7 both in vitro and in vivo.…”

Plant leads for mitigation of oral submucous fibrosis: Current scenario and future prospect

“…Its isoflavane glabridin reported downregulation of the increased myofibroblast activities caused by arecoline‐ induction and a decrease in the levels of α‐SMA, type I collagen, and TGF‐β in fBMFs (Lee et al, 2018). On the other hand, Ye et al (2020) confirmed the anti‐cancer property of isoliquiritigenin against esophageal squamous carcinoma cells (ESCC) by decreased cell proliferation as well as inhibition of EGFR activation and its downstream Akt and ERK1/2 signaling pathway. A Chinese herb Salvia miltiorrhiza famous by the name “Danshen” was also described by several authors for its anti‐fibrotic potential in addition to known antioxidant and anti‐inflammatory activity.…”

Natural Products for Esophageal Cancer Therapy: From Traditional Medicine to Modern Drug Discovery

“…Ye et al reported the anti-metastatic effects of isoliquiritigenin (ISL) as a novel remedy to treat esophageal cancer [ 34 ]. For 72 h, 20 μM of ISL resulted in the lowest survival number of cancer cell colonies in various esophageal squamous cancer cell lines by downregulating AP-1 and cyclin D1.…”

“…BALB/c mice were mainly used as animal models for research in vivo. Among apoptosis-inducing natural products, matrine, neferine, osthole, TR35, curcumin, acetyl-macrocalin B, JDA-202, oridonin, jaridonin, baohuoside-I, icariin, isoliquiritigenin, proanthocyanidin, quercetin, genistein, pristimerin, terrein, isoalantolactone, germacrone, natural borneol, gypenoside L, Rhizoma paridis saponins , avocado, black raspberry, Fructus forsythia , green husk, Marsdenia tenacissima , rhizome extract, Sutherlandia frutescens , Sutherlandia tomentosa , Daikenchuto, Rosa roxburghii Tratt , Fagopyrum cymosum , and Tonglian had little to no cytotoxicity in normal cells [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 48 , 49 , 50 , 53 , 54 , 55 , 56 , 57 ]. The rest of the research did not include cytotoxicity tests.…”