Diterpenoid Vinigrol specifically activates ATF4/DDIT3-mediated PERK arm of unfolded protein response to drive non-apoptotic death of breast cancer cells.
Pharmacol Res
; 182: 106285, 2022 08.
Article
em En
| MEDLINE
| ID: mdl-35662627
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.
Palavras-chave
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)
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
/
Diterpenos
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Fator 4 Ativador da Transcrição
/
Fator de Transcrição CHOP
Tipo de estudo:
Prognostic_studies
Limite:
Female
/
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article