Targeting cancer cell metabolism: The combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells

Issam Ben Sahra, Kathiane Laurent, Sandy Giuliano, Frédéric Larbret, Gilles Ponzio, Pierre Gounon, Yannick Le Marchand-Brustel, Sophie Giorgetti-Peraldi, Mireille Cormont, Corine Bertolotto, Marcel Deckert, Patrick Auberger, Jean François Tanti, Frédéric Bost*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

397 Scopus citations

Abstract

Targeting cancer cell metabolism is a new promising strategy to fight cancer. Metformin, a widely used antidiabetic agent, exerts antitumoral and antiproliferative action. In this study, the addition of metformin to 2-deoxyglucose (2DG) inhibited mitochondrial respiration and glycolysis in prostate cancer cells leading to a severe depletion in ATP. The combination of the two drugs was much more harmful for cancer cells than the treatment with metformin or 2DG alone, leading to 96% inhibition of cell viability in LNCaP prostate cancer cells. In contrast, a moderate effect on cell viability was observed in normal prostate epithelial cells. At the cellular level, the combination of metformin and 2DG induced p53-dependent apoptosis via the energy sensor pathway AMP kinase, and the reexpression of a functional p53 in p53-deficient prostate cancer cells restored caspase-3 activity. In addition to apoptosis, the combination of metformin and 2DG arrested prostate cancer cells in G2-M. This G2-M arrest was independent of p53 and correlated with a stronger decrease in cell viability than obtained with either drug. Finally, metformin inhibited 2DG-induced autophagy, decreased beclin 1 expression, and triggered a switch from a survival process to cell death. Our study reinforces the growing interest of metabolic perturbators in cancer therapy and highlights the potential use of the combination of metformin and 2DG as an anticancerous treatment.

Original languageEnglish (US)
Pages (from-to)2465-2475
Number of pages11
JournalCancer Research
Volume70
Issue number6
DOIs
StatePublished - Mar 15 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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