Dihydroartemisinin Inhibits the Proliferation of Esophageal Squamous Cell Carcinoma Partially by Targeting AKT1 and p70S6K

Lili Zhu; Xinhuan Chen; Yanyan Zhu; Jiace Qin; Tingting Niu; Yongwei Ding; Yang Xiao; Yanan Jiang; Kangdong Liu; Jing Lu; Wanjing Yang; Yan Qiao; Ge Jin; Junfen Ma; Ziming Dong; Jimin Zhao

doi:10.3389/fphar.2020.587470

Dihydroartemisinin Inhibits the Proliferation of Esophageal Squamous Cell Carcinoma Partially by Targeting AKT1 and p70S6K

Front Pharmacol. 2020 Nov 20:11:587470. doi: 10.3389/fphar.2020.587470. eCollection 2020.

Authors

Lili Zhu^{1

2}, Xinhuan Chen^{1

3}, Yanyan Zhu⁴, Jiace Qin^{1

3}, Tingting Niu^{1

3}, Yongwei Ding^{1

3}, Yang Xiao^{1

3}, Yanan Jiang^{1

3}, Kangdong Liu^{1

3

5}, Jing Lu^{1

3}, Wanjing Yang^{1

3}, Yan Qiao^{1

3}, Ge Jin⁶, Junfen Ma⁷, Ziming Dong^{1

3}, Jimin Zhao^{1

3

8}

Affiliations

¹ Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
² Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
³ Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou, China.
⁴ Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
⁵ The China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.
⁶ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
⁷ Department of Clinical Laboratory, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
⁸ State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China.

Abstract

Dihydroartemisinin (DHA), a sesquiterpene lactone with endoperoxide bridge, is one of the derivatives of artemisinin. In addition to having good antimalarial properties, DHA exhibits anticancer effects including against malignant solid tumors. However, the mechanism by which DHA inhibits the progression of esophageal cancer, especially esophageal squamous cell carcinoma (ESCC), is unclear. In this study, DHA was found to inhibit the proliferation of ESCC, and the underlying molecular mechanisms were explored. DHA inhibited ESCC cells proliferation and anchorage-independent growth. Flow cytometry analysis revealed that DHA significantly blocked cell cycle in the G1 phase. The results of human phospho-kinase array revealed that DHA downregulated the levels of p70S6K^T389 and p70S6K^T421/S424. Furthermore, the levels of mTOR^S2448, p70S6K^T389, p70S6K^T421/S424 and RPS6^S235/S236 were decreased after DHA treatment in KYSE30 and KYSE150 cells. We then explored the proteins targeted by DHA to inhibit the mTOR-p70S6K-RPS6 pathway. Results of the in vitro kinase assay revealed that DHA significantly inhibited phosphorylation of mTOR^S2448 by binding to AKT1 and p70S6K kinases. In vivo, DHA inhibited the tumor growth of ESCC patient-derived xenografts and weakened p-mTOR, p-p70S6K, and p-RPS6 expression in tumor tissues. Altogether, our results indicate that DHA has antiproliferative effects in ESCC cells and can downregulate mTOR cascade pathway partially by binding to AKT1 and p70S6K. Thus, DHA has considerable potential for the prevention or treatment of ESCC.

Keywords: AKT1; RPS6; dihydroartemisinin; esophageal squamous cell carcinoma; mTOR; p70S6K; patient-derived xenograft.