Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437

Citation
As. Belzacq et al., Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437, ONCOGENE, 20(52), 2001, pp. 7579-7587
Citations number
52
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
ONCOGENE
ISSN journal
0950-9232 → ACNP
Volume
20
Issue
52
Year of publication
2001
Pages
7579 - 7587
Database
ISI
SICI code
0950-9232(20011115)20:52<7579:ANTMTM>2.0.ZU;2-V
Abstract
An increasing number of experimental chemotherapeutic agents induce apoptos is by directly triggering mitochondrial membrane permeabilization (MMP). He re we examined MMP induced by lonidamine, arsenite, and the retinoid deriva tive CD437. Cells overexpressing the cytomegalovirus-encoded protein vMIA, a protein which interacts with the adenine nucleotide translocator, were st rongly protected against the MMP-inducing and apoptogenic effects of lonida mine, arsenite, and CD437. In a cell-free system, lonidamine, arsenite, and CD437 induced the permeabilization of ANT proteoliposomes, yet had no effe ct on protein-free liposomes. The ANT-dependent membrane permeabilization w as 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 l ipid bilayers containing ANT, elicited ANT channel activities with clearly distinct conductance levels of 20+/-7, 100+/-30, and 47+/-7 pS, respectivel y. Altering the ATP/ADP gradient built up on the inner mitochondrial membra ne by inhibition of glycolysis and/or oxidative phosphorylation differentia lly modulated the cytocidal potential of lonidamine, arsenite, and CD437. I nhibition of F(0)F(1)ATPase without glycolysis inhibition sensitized to lon idamine-induced cell death. In contrast, only the combined inhibition of gl ycolysis plus F(0)F(1)ATPase sensitized to arsenite-induced cell death. No sensitization to cell death induction by CD437 was achieved by glucose depl etion and/or oligomycin addition. These results indicate that ANT is a targ et of lonidamine, arsenite, and CD437 and unravel an unexpected heterogenei ty in the mode of action of these three compounds.