title: The fourth isoform of the adenine nucleotide translocator inhibits mitochondrial apoptosis in cancer cells.
abstract: The adenine nucleotide translocator (ANT) is a mitochondrial bi-functional protein, which catalyzes the exchange of ADP and ATP between cytosol and mitochondria and participates in many models of mitochondrial apoptosis. The human adenine nucleotide translocator sub-family is composed of four isoforms, namely ANT1-4, encoded by four nuclear genes, whose expression is highly regulated. Previous studies have revealed that ANT1 and 3 induce mitochondrial apoptosis, whereas ANT2 is anti-apoptotic. However, the role of the recently identified isoform ANT4 in the apoptotic pathway has not yet been elucidated. Here, we investigated the effects of stable heterologous expression of the ANT4 on proliferation, mitochondrial respiration and cell death in human cancer cells, using ANT3 as a control of pro-apoptotic isoform. As expected, ANT3 enhanced mitochondria-mediated apoptosis in response to lonidamine, a mitochondriotoxic chemotherapeutic drug, and staurosporine, a protein kinase inhibitor. Our results also indicate that the pro-apoptotic effect of ANT3 was accompanied by decreased rate of cell proliferation, alteration in the mitochondrial network topology, and decreased reactive oxygen species production. Of note, we demonstrate for the first time that ANT4 enhanced cell growth without impacting mitochondrial network or respiration. Moreover, ANT4 differentially regulated the intracellular levels of hydrogen peroxide without affecting superoxide anion levels. Finally, stable ANT4 overexpression protected cancer cells from lonidamine and staurosporine apoptosis in a manner independent of Bcl-2 expression. These data highlight a hitherto undefined cytoprotective activity of ANT4, and provide a novel dichotomy in the human ANT isoform sub-family with ANT1 and 3 isoforms functioning as pro-apoptotic while ANT2 and 4 isoforms render cells resistant to death inducing stimuli.
authors.affiliation: LGBC, CNRS UMR8159, Université Versailles-SQY, PRES Universud Paris, 45, avenue des Etats-Unis, 78035 Versailles, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Gallerne
authors.forename: Zahia
authors.initials: Z
authors.lastname: Touat
authors.forename: Zhi Xiong
authors.initials: ZX
authors.lastname: Chen
authors.forename: Cécile
authors.initials: C
authors.lastname: Martel
authors.forename: Eleonore
authors.initials: E
authors.lastname: Mayola
authors.forename: Ossama
authors.initials: O
authors.lastname: Sharaf el dein
authors.forename: Nelly
authors.initials: N
authors.lastname: Buron
authors.forename: Morgane
authors.initials: M
authors.lastname: Le Bras
authors.forename: Etienne
authors.initials: E
authors.lastname: Jacotot
authors.forename: Annie
authors.initials: A
authors.lastname: Borgne-Sanchez
authors.forename: Antoinette
authors.initials: A
authors.lastname: Lemoine
authors.forename: Christophe
authors.initials: C
authors.lastname: Lemaire
authors.forename: Shazib
authors.initials: S
authors.lastname: Pervaiz
authors.forename: Catherine
authors.initials: C
authors.lastname: Brenner
mesh_terms: D033781:Adenine Nucleotide Translocator 3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation; D048430:Cell Shape; D019610:Cytoprotection; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000032:analysis; D007191:Indazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D008928:Mitochondria / Q000502:physiology*; D000226:Mitochondrial ADP, ATP Translocases / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000502:physiology*; D010085:Oxidative Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D013481:Superoxides / Q000032:analysis
chemical_list: D033781:Adenine Nucleotide Translocator 3; D000970:Antineoplastic Agents; D007191:Indazoles; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; C518774:SLC25A31 protein, human; D013481:Superoxides; D000226:Mitochondrial ADP, ATP Translocases; D006861:Hydrogen Peroxide; D053453:Caspase 9; D019311:Staurosporine; C016371:lonidamine