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

Blaž Andlovic1, Geronimo Heilmann2, Sabrina Ninck2

  • 1Laboratory 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.

Cell Chemical Biology
|May 2, 2023
PubMed

Insights

Fusicoccanes (FCs) enhance anti-cancer activity by stabilizing 14-3-3 protein interactions. This study identifies specific 14-3-3 targets, revealing new therapeutic strategies for cancer treatment when combined with interferon alpha (IFNα).

Area of Science:

  • Natural Product Chemistry
  • Oncology
  • Proteomics

Background:

  • Fusicoccanes (FCs) are natural products with demonstrated anti-cancer properties.
  • FCs function by stabilizing 14-3-3 protein-protein interactions (PPIs).
  • Combination therapy involving FCs and interferon alpha (IFNα) shows potential for cancer treatment.

Purpose of the Study:

  • To investigate the synergistic effects of FCs combined with IFNα on various cancer cell lines.
  • To identify specific 14-3-3 PPIs modulated by IFNα and stabilized by FCs in OVCAR-3 cells using a proteomics approach.
  • To elucidate the polypharmacological mechanisms of FCs in cancer therapy.

Main Methods:

  • Proteomics analysis to identify 14-3-3 interacting proteins.
  • Biophysical and structural biology techniques to validate PPIs.
  • Transcriptome and pathway analyses to understand therapeutic mechanisms.

Main Results:

  • Identified THEMIS2, RIPK2, EIF2AK2, and LDB1 complex members as key 14-3-3 targets.
  • Confirmed FCs stabilize these specific 14-3-3 PPIs.
  • Pathway analyses suggested mechanisms for the synergistic anti-cancer effects of IFNα/FC treatment.

Conclusions:

  • FCs exhibit polypharmacological effects in cancer cells by targeting specific 14-3-3 PPIs.
  • This study identifies novel therapeutic targets within the 14-3-3 interactome for oncology.
  • The findings support the development of FCs as adjuncts in cancer therapy.
Keywords:
anti-cancercell deathprotein-protein interactionstabilizationsynergistic combination

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