Diterpenoid Vinigrol specifically activates ATF4/DDIT3-mediated PERK arm of unfolded protein response to drive non-apoptotic death of breast cancer cells

Wei，Wencheng1,2,3,4; Li，Yunfei2,3,4; Wang，Chuanxi5; Gao，Sanxing2,3,4; Zhao，Yan2,3,4; Yang，Zhenyu2,3,4; Wang，Hao2,3,4; Gao，Ziying2,3,4; Jiang，Yanxiang2,3,4; He，Yuan2,3,4; Zhao，Li6; Gao，Hao5; Yao，Xinsheng5; Hu，Yuhui2,3,4

2022-08-01

10.1016/j.phrs.2022.106285

PHARMACOLOGICAL RESEARCH   Impact Factor & Quartile

1043-6618

1096-1186

Vinigml is a natural diterpenoid with unprecedented chemical structure, driving great efforts into its total synthesis in the past decades. Despite anti-hypertension and anti-clot ever reported, comprehensive investigations on bioactions and molecular mechanisms of Vinigrol are entirely missing. Here we firstly carried out a complete functional prediction of Vinigrol using a transcriptome-based strategy coupled with multiple bioinformatic analyses and identified "anti-cancer" as the most prominent biofunction ahead of anti-hypertension and anti-depression/psychosis. Broad cytotoxicity was subsequently confirmed on multiple cancer types. Further mechanistic investigation on several breast cancer cells revealed that its anti-cancer effect was mainly through activating PERK/eIF2 alpha arm of unfolded protein response (UPR) and subsequent non-apoptotic cell death independent of caspase activities. The other two branches of UPR, IRE1 alpha and ATF6, were functionally irrelevant to Vinigrol-induced cell death. Using CRISPR/Cas9-based gene activation, repression, and knockout systems, we identified the essential contribution of ATF4 and DDIT3, not ATF6, to the death process. This study unraveled a broad anti-cancer function of Vinigrol and its underlying targets and regulatory mechanisms. It paved the way for further inspection on the structure-efficacy relationship of the whole compound family, making them a novel cluster of PERK-specific stress activators for experimental and clinical uses.

Vinigrol Unfolded protein response Anti-cancer ATF4 DDIT3 PERK

SCI

English

Corresponding

Shenzhen Key Laboratory of Gene Regulation and Systems Biology, China[ZDSYS20200811144002008] ; Shenzhen Science and Technology Program, China[KQTD20180411143432337] ; National Natural Science Foundation of China, China[81773881]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:000833425000002

ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85132448768

Web of Science

1.Harbin Institute of Technology,Harbin,150000,China
2.Shenzhen Key Laboratory of Gene Regulation and Systems Biology,School of Life Sciences,Southern University of Science and Technology,Shenzhen,518005,China
3.Department of pharmacology,School of Medicine,Southern University of Science and Technology,Shenzhen,518005,China
4.Department of Biology,School of Life Sciences,Southern University of Science and Technology,Shenzhen,518005,China
5.Institute of Traditional Chinese Medicine and Natural Products,College of Pharmacy / Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research / International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China,Jinan University,Guangzhou,510632,China
6.Department of Head and Neck Surgical Oncology,National Clinical Research Center for Cancer,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,100000,China

Wei，Wencheng,Li，Yunfei,Wang，Chuanxi,et al. Diterpenoid Vinigrol specifically activates ATF4/DDIT3-mediated PERK arm of unfolded protein response to drive non-apoptotic death of breast cancer cells[J]. PHARMACOLOGICAL RESEARCH,2022,182.

Wei，Wencheng.,Li，Yunfei.,Wang，Chuanxi.,Gao，Sanxing.,Zhao，Yan.,...&Hu，Yuhui.(2022).Diterpenoid Vinigrol specifically activates ATF4/DDIT3-mediated PERK arm of unfolded protein response to drive non-apoptotic death of breast cancer cells.PHARMACOLOGICAL RESEARCH,182.

Wei，Wencheng,et al."Diterpenoid Vinigrol specifically activates ATF4/DDIT3-mediated PERK arm of unfolded protein response to drive non-apoptotic death of breast cancer cells".PHARMACOLOGICAL RESEARCH 182(2022).