2. Academic Validation
  3. 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: [email protected].
  • 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: [email protected].
PMID: 35662627 DOI: 10.1016/j.phrs.2022.106285
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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