ANT1 silencing induces glioblastoma cell death

Adenine nucleotide translocases (ANTs) are multitask proteins involved in several aspects of cell metabolism as well as in the regulation of cell death/survival processes [1]. We investigated the role played by ANT isoform 1 in the growth of a human glioblastoma cell line (ADF cells). The silencing of ANT1 isoform by siRNA strongly reduced ADF cell viability by inducing a non-apoptotic cell death process resembling paraptosis. We demonstrated that the cell death induced by ANT1 depletion cannot be ascribed to the loss of the ATP/ADP exchange function of this protein. On the contrary, our findings indicate that ANT1-silenced cells experience oxidative stress mediated by the loss of the ANT1 uncoupling function. Several studies ascribe to ANT1 a pro-apoptotic role due to the observation that ANT1 over-expression sensitizes cells to mitochondrial depolarization or to apoptotic stimuli [2-4]. Here we demonstrate that, despite its pro-apoptotic function at high expression level, the reduction of ANT1 density under a physiological baseline impairs fundamental functions of this protein in ADF cells leading them to undertake a cell death process. 1. Palmieri F (2004) The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch 447, 689-709 2. Bauer MK, Schubert A, Rocks O & Grimm S (1999) Adenine nucleotide translocase-1, a component of the permeability transition pore, can dominantly induce apoptosis. J Cell Biol 147, 1493-502. 3. Jang JY, Choi Y, Jeon YK, Aung KC & Kim CW (2008) Over-expression of adenine nucleotide translocase 1 (ANT1) induces apoptosis and tumor regression in vivo. BMC Cancer 8, 160. 4. Zamora M, Meroño C, Viñas O & Mampel T (2004) Recruitment of NF-kappaB into mitochondria is involved in adenine nucleotide translocase 1 (ANT1)-induced apoptosis. J Biol Chem 279, 38415-23