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IFNa primes cancer cells for Fusicoccin-induced cell death via 14-3-3 PPI stabilization

ABSTRACT: The natural product family of the fusicoccanes (FCs) has been shown to display anti-cancer activity, especially when combined with established therapeutic agents. FCs stabilize 14-3-3 protein-protein interactions (PPIs). Here, we tested combinations of a small library of FCs with interferon α (IFNα) on different cancer cell lines and report a proteomics approach to identify the specific 14-3-3 PPIs that are induced by IFNα and stabilized by FCs in OVCAR-3 cells. Among the identified 14-3-3 target proteins are THEMIS2, receptor interacting protein kinase 2 (RIPK2), EIF2AK2, and several members of the LDB1 complex. Biophysical and structural biology studies confirm these 14-3-3 PPIs as physical targets of FC stabilization, and transcriptome as well as pathway analyses suggest possible explanations for the observed synergistic effect of IFNα/FC treatment on cancer cells. This study elucidates the polypharmacological effects of FCs in cancer cells and identifies potential targets from the vast interactome of 14-3-3s for therapeutic intervention in oncology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202350 | GEO | 2022/06/02

REPOSITORIES: GEO

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Polypharmacological perturbation of the 14-3-3 adaptor protein interactome stimulates neurite outgrowth

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2020-03-31 | PXD017317 | Pride

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Expression data from OVCAR-3 cells overexpressing histone H1.3

2014-10-31 | E-GEOD-61692 | biostudies-arrayexpress

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2020-01-13 | PXD016160 | Pride

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2021-03-16 | GSE168927 | GEO

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Project description:We overexpressed EIF2AK2 in HeLa cells to study EIF2AK2-regulated genes using RNA-seq technology, followed by bioinformatic analysis of target genes of EIF2AK2-regulated transcriptional factors (TFs)

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