The fourth isoform of the adenine nucleotide translocator inhibits mitochondrial apoptosis in cancer cells

Adenine nucleotide translocase family: four isoforms for apoptosis modulation in cancer

“…Thus, it has been speculated that (1) ANT2 could function in a reverse manner to import ATP into the mitochondrial matrix to compensate for the reduced mitochondrial ATP production in cancer cells (Chevrollier et al, 2005a) and (2) could interact preferentially with Bcl-2 to favor a stabilization of mitochondrial membranes through the inhibition of MMP (Belzacq et al, 2003). Thus, we observed that on the one hand the decrease of ANT2 levels by small-interfering RNA knock-down sensitized cells to apoptosis induction , but on the other hand increased ANT2 levels by stable overexpression in various cell lines (for example HT29 and HeLa cells) promoted chemoresistance (Gallerne et al, 2010). For instance, ANT2 downregulation renders HeLa cells resistant to Lonidamine, an anti-cancer agent whose effect is based on the induction of the mitochondrial apoptosis pathway through the ANT targeting (Ravagnan et al, 1999;Belzacq et al, 2001a;Gallerne et al, 2010).…”

“…Thus, we observed that on the one hand the decrease of ANT2 levels by small-interfering RNA knock-down sensitized cells to apoptosis induction , but on the other hand increased ANT2 levels by stable overexpression in various cell lines (for example HT29 and HeLa cells) promoted chemoresistance (Gallerne et al, 2010). For instance, ANT2 downregulation renders HeLa cells resistant to Lonidamine, an anti-cancer agent whose effect is based on the induction of the mitochondrial apoptosis pathway through the ANT targeting (Ravagnan et al, 1999;Belzacq et al, 2001a;Gallerne et al, 2010). Accordingly, suppression of ANT2 by small-interfering RNA in human breast cancer cells induces apoptosis and prevents tumor growth in vitro and in vivo (Jang et al, 2008b).…”

“…The antiapoptotic activity of ANT4 isoform could be mediated by modulation of the ROS steady-state levels. As in this experimental cellular model (Gallerne et al, 2010), the various ANT isoforms are present, this suggests a possible complex regulatory balance between ANT pro-and anti-apoptotic isoforms and other apoptosis regulatory proteins (that is Bcl-2, GST, catalase) (Gallerne et al, 2010). Owing to its recent discovery, the specific role of ANT4 in cancer has not yet been investigated.…”

“…Moreover, the presence of a COUP-TF-binding sequence element confers transcriptional repression, thereby negatively regulating hormonal induction of target genes (Cooney et al, 1992). In human cancer cell lines (for example HeLa and HT29), ANT4 overexpression inhibits apoptotic signaling, especially mitochondriamediated cell death (Gallerne et al, 2010). Thus, ANT4 prevents the loss of mitochondrial transmembrane potential (DCm), the opening of PTPC, the activation of effector caspase-9 and nuclear alterations.…”

“…More recently, a third major breakthrough has been made in terms of role of ANT in apoptosis. Thus, ANT is expressed as four tissue-specific isoforms, ANT1 to ANT4, and we and others postulated that each ANT isoform might have a specific role in influencing cell fate, notably in cancer cells (Bauer et al, 1999;Zamora et al, 2004a;Le Bras et al, 2006;Gallerne et al, 2010). In this review, we recapitulate our knowledge of the role that the various isoforms of ANT play in apoptosis, examine the expression and the function of the four ANT isoforms in cancer cells and discuss recent evidence to propose a novel classification of ANT isoforms and their function in cancer cell death.…”