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Metformin sensitizes triple-negative breast cancer to proapoptotic TRAIL receptor agonists by suppressing XIAP

Elena Strekalova1, Dmitry Malin1, Harisha Rajanala1

  • 1Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, MFCB 4144, 1685 Highland Avenue, Madison, WI, 53705, USA.

Breast Cancer Research and Treatment
|March 22, 2017
PubMed
Abstract

Insights

Metformin, a diabetes drug, enhances the effectiveness of TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists against triple-negative breast cancer (TNBC) by reducing XIAP levels. This combination therapy shows promise for treating metastatic TNBC.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists show preclinical promise but lack clinical efficacy.
  • Identifying agents to enhance TRAIL agonist activity is crucial for breast cancer treatment.

Purpose of the Study:

  • To investigate if metformin, a diabetes drug, can sensitize triple-negative breast cancer (TNBC) cells to TRAIL receptor agonists.
  • To elucidate the molecular mechanisms underlying metformin's potential sensitizing effects.

Main Methods:

  • TNBC cell lines were treated with TRAIL receptor agonists and/or metformin.
  • Assessed effects on cell survival, caspase activation, and expression of TRAIL receptors and XIAP.
  • Investigated XIAP's role using RNA interference and evaluated in vivo antitumor effects in a metastatic TNBC model.

Main Results:

  • Metformin sensitized various TNBC cells to TRAIL receptor agonists.
  • Metformin reduced XIAP protein levels, a key inhibitor of TRAIL-induced apoptosis.
  • XIAP silencing mimicked metformin's TRAIL-sensitizing effects.
  • Metformin enhanced TRAIL's antitumor activity in a metastatic TNBC mouse model.

Conclusions:

  • Metformin enhances the efficacy of TRAIL receptor agonists in TNBC.
  • The findings support further translational research combining metformin and TRAIL agonists.
Keywords:
ApoptosisBreast cancerMetastasisMetforminTRAILTherapeutics

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