The Translocator Protein (TSPO) is a high-affinity cholesterol-binding protein, located in the outer mitochondrial membrane, where takes part in the mitochondrial permeability transition pore (MPTP) (1, 2). Its expression has been found altered in different pathological conditions, including cancer (3). Although the functional role of TSPO has been largely explored for more than 30 y, its role in cancer pathophysiology is still not completely understood, and data from literature are often in contrast (4,5). Much controversy on TSPO functions has been discussed extensively above all in relation to the high dose of TSPO ligands required to inhibit cancer cell viability: the anticancer effective dose reported in literature is in fact much higher than the ligand affinity to TSPO binding sites (up to 1000 times). Based on this data, a synthetized compound that binds irreversibly to TSPO (IRDE-MPIGA, Taliani et al., 2010) was used in order to better understand the functional role of TSPO in cancer. The covalent nature of the binding allowed us to use IRDE-MPIGA at concentrations close to its affinity to TSPO (low nanomolar dose), abolishing the dissociation of TSPO-ligand interaction and other high-dose related non-specific effects. We evidenced that 10nM IRDE-MPIGA induced 1) in isolated mitochondria, collapse of ΔΨm; 2) in human glioblastoma cells, immediate ΔΨm collapse, apoptosis (as revealed by phosphatidylserine externalization) and increase in steroidogenesis. These results directly support the thesis that the selective activation of TSPO serves to trigger the death machine in cancer cells.
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