Instruct: Identify the main category of Biorxiv papers based on the titles and abstracts
Query: Diterpenoid Vinigrol activates ATF4/DDIT3-mediated PERK/eIF2 arm of unfolded protein response to drive breast cancer cell death Vinigrol is a natural diterpenoid with unprecedented chemical structure, driving great efforts into its total synthesis and the chemical analogs in the past decades. Despite its pharmacological efficacies reported on anti-hypertension and anti-clot, comprehensive functional investigations on Vinigrol and the underlying molecular mechanisms are entirely missing. In this study, we carried out a complete functional prediction of Vinigrol using a transcriptome-based strategy, Connectivity Map, and identified "anti-cancer" as the most prominent biofunction ahead of anti-hypertension and anti-depression/psychosis. A broad cytotoxicity was subsequently confirmed on multiple cancer types. Further mechanistic investigation on MCF7 cells revealed that its anti-cancer effect is mainly through activating PERK/eIF2 arm of unfolded protein response (UPR) and subsequent upregulation of p53/p21 to halt the cell cycle. The other two branches of UPR, IRE1 and ATF6, are functionally irrelevant to Vinigrol-induced cell death. CRISPR/Cas9-based gene activation, repression, and knockout systems identified essential contribution of ATF4/DDIT3 not ATF6 to the death process. This study unraveled a broad anti-cancer function of Vinigrol and its underlying targets and regulatory mechanisms, and also paved the way for further inspection on the structure-efficacy relationship of the whole compound family, making them a novel cluster of chemical hits for cancer therapy.
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The categories of this paper are: bioengineering
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The categories of this paper are: cognition
1
The categories of this paper are: bioinformatics
5
The categories of this paper are: cell
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The categories of this paper are: biochemistry
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The categories of this paper are: communication
3
The categories of this paper are: evolutionary
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The categories of this paper are: genomics
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The categories of this paper are: immunology
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The categories of this paper are: cancer
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The categories of this paper are: paleontology
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The categories of this paper are: biology
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The categories of this paper are: synthetic
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The categories of this paper are: neuroscience
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The categories of this paper are: epidemiology
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The categories of this paper are: plant