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A novel Diels–Alder adduct of mulberry leaves exerts anticancer effect through autophagy-mediated cell death

Authors: Yu-han Shu1,2, Hua-hua Yuan1, Meng-ting Xu1, Ye-ting Hong3, Cheng-cheng Gao1, Zhi-pan Wu1, Hao-te Han1, Xin Sun4, Rui-lan Gao5, Si-fu Yang4, Shou-xin Li1,6, Jing-kui Tian1,6, Jian-bin Zhang2
1 College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310058, China
2 Clinical Research Institute, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
3 Hangzhou Medical College, Hangzhou 310053, China
4 epartment of Oncology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
5 Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China
6 Key Laboratory for Biomedical Engineering of Ministry of Education, Zhejiang-Malaysia Joint Research Center for Traditional Medicine, Zhejiang University, Hangzhou 310058, China
Correspondence to: Jing-kui Tian: tjk@zju.edu.cn, Jian-bin Zhang: zhangjianbin@hmc.edu.cn,
DOI: 10.1038/s41401-020-0492-5
Received: 4 April 2020
Accepted: 22 July 2020
Advance online: 19 August 2020

Abstract

Guangsangon E (GSE) is a novel Diels–Alder adduct isolated from leaves of Morus alba L, a traditional Chinese medicine widely applied in respiratory diseases. It is reported that GSE has cytotoxic effect on cancer cells. In our research, we investigated its anticancer effect on respiratory cancer and revealed that GSE induces autophagy and apoptosis in lung and nasopharyngeal cancer cells. We first observed that GSE inhibits cell proliferation and induces apoptosis in A549 and CNE1 cells. Meanwhile, the upregulation of autophagosome marker LC3 and increased formation of GFP–LC3 puncta demonstrates the induction of autophagy in GSE-treated cells. Moreover, GSE increases the autophagy flux by enhancing lysosomal activity and the fusion of autophagosomes and lysosomes. Next, we investigated that endoplasmic reticulum (ER) stress is involved in autophagy induction by GSE. GSE activates the ER stress through reactive oxygen species (ROS) accumulation, which can be blocked by ROS scavenger NAC. Finally, inhibition of autophagy attenuates GSE-caused cell death, termed as “autophagy-mediated cell death.” Taken together, we revealed the molecular mechanism of GSE against respiratory cancer, which demonstrates great potential of GSE in the treatment of representative cancer.
Keywords: Guangsangon E; autophagy; ER stress; respiratory cancer

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