Apigenin Induces Autophagy and Cell Death by Targeting EZH2 under Hypoxia Conditions in Gastric Cancer Cells.

Tae Woo Kim,Hee Gu Lee

doi:10.3390/ijms222413455

Abstract

Hypoxia is a major obstacle to gastric cancer (GC) therapy and leads to chemoresistance as GC cells are frequently exposed to the hypoxia environment. Apigenin, a flavonoid found in traditional medicine, fruits, and vegetables and an HDAC inhibitor, is a powerful anti-cancer agent against various cancer cell lines. However, detailed mechanisms involved in the treatment of GC using APG are not fully understood. In this study, we investigated the biological activity of and molecular mechanisms involved in APG-mediated treatment of GC under hypoxia. APG promoted autophagic cell death by increasing ATG5, LC3-II, and phosphorylation of AMPK and ULK1 and down-regulating p-mTOR and p62 in GC. Furthermore, our results show that APG induces autophagic cell death via the activation of the PERK signaling, indicating an endoplasmic reticulum (ER) stress response. The inhibition of ER stress suppressed APG-induced autophagy and conferred prolonged cell survival, indicating autophagic cell death. We further show that APG induces ER stress- and autophagy-related cell death through the inhibition of HIF-1α and Ezh2 under normoxia and hypoxia. Taken together, our findings indicate that APG activates autophagic cell death by inhibiting HIF-1α and Ezh2 under hypoxia conditions in GC cells.

Highlights

Natural compounds extracted from many plants, including fruits, vegetables, and traditional medicines, have properties of high bioavailability, low side effects, and potent pharmacological activity [1]
We identified that APG causes autophagic cell death via the PERK–ATF4– CHOP axis and suppresses hypoxia-inducible factor 1α (HIF-1α) and Ezh2 by inhibiting mammalian target of rapamycin (mTOR) signaling in gastric cancer (GC)
APG mediated a dramatic reduction in cell viability in various GC cell types when compared to the control, but there was no change in MRC5 (Figure 1A)

Summary

Introduction

Natural compounds extracted from many plants, including fruits, vegetables, and traditional medicines, have properties of high bioavailability, low side effects, and potent pharmacological activity [1]. These natural products are often readily available in their many different structures, meaning that a novel compound can be developed from them [2]. According to recent studies on flavonoids, a compound known as hesperetin exerts anti-cancer effects by inducing apoptotic cell death via inhibition of Bax and Bcl-2 and ROS production [6]. Though APG induces apoptosis and cell death via NF-κB, ROS, and inflammation in gastric cancer, deep and detailed mechanisms underlying these activities remain unclear

Methods

Results

Conclusion