Zhu Lili, Chen Xinhuan, Zhu Yanyan, Qin Jiace, Niu Tingting, Ding Yongwei, Xiao Yang, Jiang Yanan, Liu Kangdong, Lu Jing, Yang Wanjing, Qiao Yan, Jin Ge, Ma Junfen, Dong Ziming, Zhao Jimin
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Front Pharmacol. 2020 Nov 20;11:587470. doi: 10.3389/fphar.2020.587470. eCollection 2020.
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 and p70S6K. Furthermore, the levels of mTOR, p70S6K, p70S6K and RPS6 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 kinase assay revealed that DHA significantly inhibited phosphorylation of mTOR by binding to AKT1 and p70S6K kinases. , 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.
双氢青蒿素（DHA）是一种带有内过氧化物桥的倍半萜内酯，是青蒿素的衍生物之一。除了具有良好的抗疟特性外，DHA还表现出抗癌作用，包括对恶性实体瘤的作用。然而，DHA抑制食管癌尤其是食管鳞状细胞癌（ESCC）进展的机制尚不清楚。在本研究中，发现DHA可抑制ESCC的增殖，并对其潜在的分子机制进行了探索。DHA抑制ESCC细胞的增殖和锚定非依赖性生长。流式细胞术分析显示，DHA显著阻断细胞周期于G1期。人磷酸激酶阵列结果显示，DHA下调p70S6K和p70S6K的水平。此外，在KYSE30和KYSE150细胞中，DHA处理后mTOR、p70S6K、p70S6K和RPS6的水平降低。然后，我们探索了DHA靶向抑制mTOR-p70S6K-RPS6途径的蛋白质。激酶分析结果显示，DHA通过与AKT1和p70S6K激酶结合，显著抑制mTOR的磷酸化。此外，DHA抑制ESCC患者来源异种移植瘤的肿瘤生长，并减弱肿瘤组织中p-mTOR、p-p70S6K和p-RPS6的表达。总之，我们的结果表明，DHA对ESCC细胞具有抗增殖作用，并且可以通过与AKT1和p70S6K结合，部分下调mTOR级联途径。因此，DHA在预防或治疗ESCC方面具有相当大的潜力。
