Artesunate Suppresses the Proliferation and Development of Estrogen Receptor-α-Positive Endometrial Cancer in HAND2-Dependent Pathway.

Xianghua Yin,Xiyue Huang,Ping Yu,Yixuan Wu,Jiayan Huang,Qi Zhao,Tingting Dang,Yan Liu,Jiarui Qin,Yacui Tian

doi:10.3389/fcell.2020.606969

Abstract

Endometrial cancer (EC) is a common leading cause of cancer-related death in women, which is associated with the increased level of estrogen in the body. Artesunate (ART), an active compound derived from Artemisia annua L., exerted antitumor properties in several cancer types. However, the role of artesunate and the molecular basis on EC remains unclear. Here, we aimed to explore the effects and mechanisms of artesunate. Our results identified that estrogen receptor-α (ER-α) was a key factor for the type I EC (ER-α-positive), which might suppress the downstream LKB1/AMPK/mTOR pathway. Besides, we found ART significantly inhibited tumor proliferation in a dose-dependent manner. Mechanistic studies identified that ART led to tumor cell apoptosis and cell cycle arrest by downregulating the ER-α expression and activating the LKB1/AMPK/mTOR pathway. In addition, we found ART could increase the expression of heart and neural crest derivatives expressed 2 (HAND2) in the ER-α-positive EC cells, which could interact with ER-α. Through the gain-and loss-function experiments, we showed that over expression of HAND2 repressed the proliferation and migration of ER-α-positive EC cells via inhibition of ER-α expression. HAND2 knockdown increased ER-α expression and alleviated the antitumor effect of ART in vitro and in vivo. Overall, our study first showed that ART could be an effective antitumor agent through modulating ER-α-mediated LKB1/AMPK/mTOR pathway in the HAND2 dependent manner. Our findings provide an effective therapeutic agent for ER-α-positive EC treatment.

Highlights

Endometrial cancer (EC) is a common cause of cancer-related death worldwide, affecting about 21% of women (Sorosky, 2012; Brooks et al, 2019)
Our results identified that estrogen receptor-α (ER-α) was a key factor for the type I EC (ER-α-positive), which might suppress the downstream liver kinase B 1 (LKB1)/AMP-activated protein kinase (AMPK)/mTOR pathway
We detected the expression level of ER-α in our clinical samples (n = 100) and found that compared with the normal tissue samples (n = 100), a six-fold upregulation of ER-α expression was detected in the type I EC samples (n = 72), while a 50% reduction was observed in the type II EC samples (n = 28), suggesting that more than 72% EC was estrogen-sensitive (Figure 1A)

Summary

Introduction

Endometrial cancer (EC) is a common cause of cancer-related death worldwide, affecting about 21% of women (Sorosky, 2012; Brooks et al, 2019). Multiple risk factors contributed to EC formation, including reproductive factors, imbalanced hormone, age, and obesity (Amant et al, 2005). Researchers identified that sustained stimulation with exogenous estrogen is a crucial risk factor in accelerating the progression of ER-related cancers. Almost 80% of the EC are categorized into type I EC [endometrioidtype endometrial cancer (EEC)] which is estrogen-positive and present at the early stage with an excellent prognosis (Amant et al, 2005). Studies revealed that ER-α rapidly modulated the AMP-activated protein kinase (AMPK) signaling pathway, which involved in the modulation of cell proliferation, differentiation, and death. In many types of cancer, including EC, AMPK was inactivated due to the high glucose metabolic conditions (Han et al, 2015). The role of the ER-α-mediated LKB1/AMPK pathway in EC, is still unexplored

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