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Drug Repositioning Inferred from E2F1-Coregulator Interactions Studies for the Prevention and Treatment of Metastatic

Deborah Goody1, Shailendra K Gupta2, David Engelmann1

  • 1Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany.

Theranostics
|March 15, 2019
PubMed

Insights

This study identifies a protein complex (E2F1:MTA1) that drives cancer metastasis. FDA-approved drug argatroban disrupts this complex, offering a new strategy to prevent metastasis and cancer relapse.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Metastasis management is a significant challenge in cancer therapy.
  • The E2F1 protein promotes tumor progression through protein-protein interactions (PPI) with coregulators, activating prometastatic genes.

Purpose of the Study:

  • To identify E2F1-interacting coregulators involved in metastasis.
  • To investigate the therapeutic potential of inhibiting E2F1-coregulator interactions.

Main Methods:

  • Integrated high-throughput co-immunoprecipitation/mass spectrometry, GST-pull-down assays, and structure modeling to identify E2F1-coregulators.
  • Bioinformatics-based pharmacophore modeling for PPI inhibitor discovery.
  • Validated gene expression and regulation using qRT-PCR, immunoblotting, chromatin IP, and luciferase assays; assessed metastasis in vitro and in vivo mouse models.

Main Results:

  • Identified metastasis-associated protein 1 (MTA1) as a key E2F1 coregulator, forming a complex (E2F1:MTA1) that upregulates hyaluronan synthase 2 (HAS2) and promotes cell motility.
  • Disrupting the E2F1:MTA1 interaction reduced hyaluronan synthesis and tumor-associated macrophage infiltration, suppressing metastasis.
  • The FDA-approved drug argatroban abrogated the E2F1:MTA1 complex, preventing metastasis and relapse in melanoma and pancreatic cancer models by targeting the E2F1:MTA1/HAS2 axis.

Conclusions:

  • Propose argatroban as a novel antimetastatic drug targeting E2F1-coregulator interactions.
  • Suggests that patients with the E2F1/MTA1/HAS2 signature may benefit from argatroban repositioning for cancer treatment.
Keywords:
E2F1-coregulatorMTA1drug repositioningmetastasispharmacophore modeling

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