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

Blaž Andlovic; Geronimo Heilmann; Sabrina Ninck; Sebastian A Andrei; Federica Centorrino; Yusuke Higuchi; Nobuo Kato; Luc Brunsveld; Michelle Arkin; Sascha Menninger; Axel Choidas; Alexander Wolf; Bert Klebl; Farnusch Kaschani; Markus Kaiser; Jan Eickhoff; Christian Ottmann

doi:10.1016/j.chembiol.2023.04.005

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

Cell Chem Biol. 2023 Jun 15;30(6):573-590.e6. doi: 10.1016/j.chembiol.2023.04.005. Epub 2023 May 1.

Authors

Blaž Andlovic¹, Geronimo Heilmann², Sabrina Ninck², Sebastian A Andrei³, Federica Centorrino³, Yusuke Higuchi⁴, Nobuo Kato⁴, Luc Brunsveld³, Michelle Arkin⁵, Sascha Menninger⁶, Axel Choidas⁶, Alexander Wolf⁶, Bert Klebl⁶, Farnusch Kaschani², Markus Kaiser², Jan Eickhoff⁶, Christian Ottmann⁷

Affiliations

¹ Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, the Netherlands; Lead Discovery Center GmbH, 44227 Dortmund, Germany.
² Chemical Biology, Center of Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, Universitätsstr. 2, 45117 Essen, Germany.
³ Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, the Netherlands.
⁴ The Institute of Scientific and Industrial Research, Osaka University, Osaka, Ibaraki, Japan.
⁵ Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Lead Discovery Center GmbH, 44227 Dortmund, Germany.
⁷ Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, the Netherlands. Electronic address: c.ottmann@tue.nl.

PMID: 37130519
DOI: 10.1016/j.chembiol.2023.04.005

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.

Keywords: anti-cancer; cell death; protein-protein interaction; stabilization; synergistic combination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Cell Death
Cell Line, Tumor
Female
Humans
Interferon-alpha* / pharmacology
Ovarian Neoplasms*

Substances

Interferon-alpha
fusicoccin