Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells.
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 G(2)-M. This G(2)-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.
Ben Sahra
Issam
I
Faculté de Médecine, Université de Nice Sophia-Antipolis, Institut Signalisation et Pathologies, Institut National de la Sante et de la Recherche Medicale, U895, Nice, France.
Laurent
Kathiane
K
Giuliano
Sandy
S
Larbret
Frédéric
F
Ponzio
Gilles
G
Gounon
Pierre
P
Le Marchand-Brustel
Yannick
Y
Giorgetti-Peraldi
Sophie
S
Cormont
Mireille
M
Bertolotto
Corine
C
Deckert
Marcel
M
Auberger
Patrick
P
Tanti
Jean-François
JF
Bost
Frédéric
F
D000255:Adenosine Triphosphate / Q000172:deficiency / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003847:Deoxyglucose / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000255:Adenosine Triphosphate; D008687:Metformin; D003847:Deoxyglucose; D000263:Adenylate Kinase