Isoliquiritigenin induces apoptosis and autophagy and inhibits endometrial cancer growth in mice.

Chi-Hao Wu,Hsin-Yuan Chen,Tzong-Ming Shieh,Li-Chun Lin,Chia-Woei Wang,Kai-Lee Wang,Shih-Min Hsia,Tsui-Chin Huang

doi:10.18632/oncotarget.12369

Abstract

Endometrial cancer is the most common cancer in women, typically with onset after menopause. Isoliquiritigenin (ISL), a licorice flavonoid, was previously shown to have anti-oxidant, anti-inflammatory, and tumor suppression effects. In this study, we investigated the anti-tumor effect of ISL on human endometrial cancer both in vitro and in vivo. We used telomerase-immortalized human endometrial stromal cells (T-HESCs) and human endometrial cancer cell lines (Ishikawa, HEC-1A, and RL95-2 cells) as targets. The effects of ISL on cell proliferation, cell cycle regulation, and apoptosis or autophagy-related protein expression were examined. In addition, we conducted in vivo experiments to confirm the inhibitory effects of ISL on cancer cells. ISL significantly inhibited the viability of cancer cells in a dose- and time-dependent manner but with little toxicity on normal cells. In addition, flow cytometry analysis indicated that ISL induced sub-G1 or G2/M phase arrest. ISL treatment activated the extracellular signal regulated kinase signaling pathway to enhance the protein expression of caspase-7/LC3BII associated with apoptosis/autophagy. Furthermore, ISL suppressed xenograft tumor growth in vivo. Taken together, these findings suggest that ISL may induce apoptosis, autophagy, and cell growth inhibition, indicating its potential as a therapeutic agent for human endometrial cancer.

Highlights

Endometrial cancer is the most common malignant tumor of the female reproductive tract, with onset typically after menopause
ISL suppressed xenograft tumor growth in vivo. These findings suggest that ISL may induce apoptosis, autophagy, and cell growth inhibition, indicating its potential as a therapeutic agent for human endometrial cancer
We found that ISL inhibited proliferation and cell cycle arrest in G1 or G2/M phase, promoted apoptosis and autophagy, and suppressed the growth of xenograft tumors in vivo

Summary

Introduction

Endometrial cancer is the most common malignant tumor of the female reproductive tract, with onset typically after menopause. In Taiwan, the incidence rate of this cancer from 2006 to 2010 was 37.52 per 100,000 women per year in women aged between 55 and 59 years [1]. The incidence rate in younger women has been increasing, with up to 14% of cases diagnosed in premenopausal women. Women younger than 40 years account for 4% of endometrial cancer cases [2,3]. Endometrial cancers are usually treated with surgery, radiation, hormones, and chemotherapy, depending on the stage of disease. For endometrial precancer patients who desire to maintain their fertility, hysterectomy may not be an ideal management choice

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