Chemosensitization by knockdown of adenine nucleotide translocase-2.
Mitochondrial membrane permeabilization (MMP) is a rate-limiting step of apoptosis, including in anticancer chemotherapy. Adenine nucleotide translocase (ANT) mediates the exchange of ADP and ATP on the inner mitochondrial membrane in healthy cells. In addition, ANT can cooperate with Bax to form a lethal pore during apoptosis. Humans possess four distinct ANT isoforms, encoded by four genes, whose transcription depends on the cell type, developmental stage, cell proliferation, and hormone status. Here, we show that the ANT2 gene is up-regulated in several hormone-dependent cancers. Knockdown of ANT2 by RNA interference induced no major changes in the aspect of the mitochondrial network or cell cycle but provoked minor increase in mitochondrial transmembrane potential and reactive oxygen species level and reduced intracellular ATP concentration without affecting glycolysis. At expression and functional levels, ANT2 depletion was not compensated by other ANT isoforms. Most importantly, ANT2, but not ANT1, silencing facilitated MMP induction by lonidamine, a mitochondrion-targeted antitumor compound already used in clinical studies for breast, ovarian, glioma, and lung cancer as well as prostate adenoma. The combination of ANT2 knockdown with lonidamine induced apoptosis irrespective of the Bcl-2 status. These data identify ANT2 as an endogenous inhibitor of MMP and suggest that its selective inhibition could constitute a promising strategy of chemosensitization.
Le Bras
Morgane
M
Centre National de la Reserche Scientifique UMR 8159, Université de Versailles/St. Quentin, Versailles, France.
Borgne-Sanchez
Annie
A
Touat
Zahia
Z
El Dein
Ossama Sharaf
OS
Deniaud
Aurélien
A
Maillier
Evelyne
E
Lecellier
Gael
G
Rebouillat
Dominique
D
Lemaire
Christophe
C
Kroemer
Guido
G
Jacotot
Etienne
E
Brenner
Catherine
C
D033741:Adenine Nucleotide Translocator 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D033742:Adenine Nucleotide Translocator 2 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010539:Permeability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
D033741:Adenine Nucleotide Translocator 1; D033742:Adenine Nucleotide Translocator 2; D000970:Antineoplastic Agents; D007191:Indazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D000255:Adenosine Triphosphate; C016371:lonidamine