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

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

  • Pharmacol Res. 2022 Aug;182:106285. doi: 10.1016/j.phrs.2022.106285.
Wencheng Wei 1 Yunfei Li 2 Chuanxi Wang 3 Sanxing Gao 2 Yan Zhao 2 Zhenyu Yang 2 Hao Wang 2 Ziying Gao 2 Yanxiang Jiang 2 Yuan He 2 Li Zhao 4 Hao Gao 5 Xinsheng Yao 3 Yuhui Hu 6
Affiliations

Affiliations

  • 1 Harbin Institute of Technology, Harbin 150000, China; Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China; Department of pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518005, China; Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China.
  • 2 Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China; Department of pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518005, China; Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China.
  • 3 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.
  • 4 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.
  • 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. Electronic address: tghao@jnu.edu.cn.
  • 6 Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China; Department of pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518005, China; Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China. Electronic address: huyh@sustech.edu.cn.
Abstract

Vinigrol 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/eIF2α arm of unfolded protein response (UPR) and subsequent non-apoptotic cell death independent of Caspase activities. The other two branches of UPR, IRE1α 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.

Keywords

ATF4; Anti-cancer; Brefeldin A (BFA) (PubChem CID: 5287620); Cycloheximide (PubChem CID: 6197); DDIT3; Doxorubicin (PubChem CID: 31703); GSK2606414 (PubChem CID: 53469448); PERK; Trans-ISRIB (PubChem CID: 1011240); Unfolded protein response; Vinigrol; Vinigrol (PubChem CID: 5492644); zVAD-FMK (PubChem CID: 5497174).

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