Abstract
An increasing number of experimental chemotherapeutic agents induce apoptosis by directly triggering mitochondrial membrane permeabilization (MMP). Here we examined MMP induced by lonidamine, arsenite, and the retinoid derivative CD437. Cells overexpressing the cytomegalovirus-encoded protein vMIA, a protein which interacts with the adenine nucleotide translocator, were strongly protected against the MMP-inducing and apoptogenic effects of lonidamine, arsenite, and CD437. In a cell-free system, lonidamine, arsenite, and CD437 induced the permeabilization of ANT proteoliposomes, yet had no effect on protein-free liposomes. The ANT-dependent membrane permeabilization was inhibited by the two ANT ligands ATP and ADP, as well as by recombinant Bcl-2 protein. Lonidamine, arsenite, and CD437, added to synthetic planar lipid bilayers containing ANT, elicited ANT channel activities with clearly distinct conductance levels of 20±7, 100±30, and 47±7 pS, respectively. Altering the ATP/ADP gradient built up on the inner mitochondrial membrane by inhibition of glycolysis and/or oxidative phosphorylation differentially modulated the cytocidal potential of lonidamine, arsenite, and CD437. Inhibition of F0F1ATPase without glycolysis inhibition sensitized to lonidamine-induced cell death. In contrast, only the combined inhibition of glycolysis plus F0F1ATPase sensitized to arsenite-induced cell death. No sensitization to cell death induction by CD437 was achieved by glucose depletion and/or oligomycin addition. These results indicate that ANT is a target of lonidamine, arsenite, and CD437 and unravel an unexpected heterogeneity in the mode of action of these three compounds.
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Abbreviations
- ANT:
-
adenine nucleotide translocator
- AIF:
-
apoptosis inducing factor
- Ars:
-
arsenic trioxide
- Atr:
-
atractyloside
- CD437:
-
6[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid
- Diamide:
-
diazenedicarboxylic acid bis 5N, N-dimethylamide, DiOC6(3), 3,3′dihexyloxacarbocyanine iodide
- ΔΨm:
-
mitochondral transmembrane potential
- HE:
-
hydroethidine
- LND:
-
lonidamine
- MMP:
-
mitochondrial membrane permeabilization
- 4-MU:
-
4-methylumbelliferone
- 4-MUP:
-
4-methylumbelliferylphosphate
- PI:
-
propidium iodide
- ROS:
-
reactive oxygen species
- VDAC:
-
voltage-dependent anion channel
- vMIA:
-
viral mitochondria-localized inhibitor of apoptosis
- Vpr:
-
viral protein R
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Acknowledgements
We thank Dr V Goldmacher (Immunogen Inc, Cambridge, MA, USA) for vMIA transfected Hela cells and critical reading of the manuscript, Dr N Israel (Pasteur Institute, Paris) for Bcl-2 transfected Jurkat cells, Z Xie and JC Reed (Burnham Institute, La Jolla, CA, USA) for recombinant Bcl-2, the Angelini Research Institute (Rome, Italy) for LND, Galderma (Sophia Antipolis, France) for CD437 gift, D Decaudin and MF Poupon for technical advice. This work has been supported by a special grant from the Ligue Nationale contre le Cancer as well as by grants from ANRS (to G Kroemer), FRM (to G Kroemer and C Brenner), Association pour la Recherche sur le Cancer (to C Brenner), French Ministry of Science (to C Brenner), and the European Commission (QLG1-1999-00739 to G Kroemer). HLA Vieira receives a fellowship from the Fundação para a Ciência e a Tecnologia PRAXIS XXI, Portugal; A-S Belzacq from ARC, CE Hamel from the Ligue contre le Cancer, Val de Marne, I Cohen and D Haouzi from the Ligue Nationale contre le Cancer.
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Belzacq, AS., El Hamel, C., Vieira, H. et al. Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437. Oncogene 20, 7579–7587 (2001). https://doi.org/10.1038/sj.onc.1204953
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DOI: https://doi.org/10.1038/sj.onc.1204953
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