Ligands of the mitochondrial 18 kDa translocator protein attenuate apoptosis of human glioblastoma cells exposed to erucylphosphohomocholine

• Published in: Cellular oncology : the official journal of the International Society for Cellular Oncology Vol. 30; no. 5; pp. 435 - 450
• Main Authors: Kugler, Wilfried, Veenman, Leo, Shandalov, Yulia, Leschiner, Svetlana, Spanier, Ilana, Lakomek, Max, Gavish, Moshe
• Format: Journal Article
• Language: English
• Published: Netherlands IOS Press 2008; Hindawi Limited
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; Benzodiazepinones - pharmacology; Blotting, Western; Caspases - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cytochromes c - drug effects; Erucic Acids - pharmacology; Glioblastoma - metabolism; Humans; Isoquinolines - pharmacology; Ligands; Membrane Potential, Mitochondrial - drug effects; Mitochondrial Membrane Transport Proteins - drug effects; Mitochondrial Membrane Transport Proteins - metabolism; Other; Phosphorylcholine - analogs & derivatives; Phosphorylcholine - pharmacology; Receptors, GABA - metabolism
• ISSN: 1570-5870; 1875-8606
• DOI: 10.3233/CLO-2008-0431

We have previously shown that the anti-neoplastic agent erucylphosphohomocholine (ErPC3) requires the mitochondrial 18 kDa Translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor (PBR), to induce cell death via the mitochondrial apoptosis pathway.
With the aid of the dye JC-1 and cyclosporin A, applied to glioblastoma cells, we now investigated the significance of opening of the mitochondrial permeability transition pore (MPTP) for ErPC3-induced apoptosis in interaction with the TSPO ligands, PK 11195 and Ro5 4864. Furthermore, we measured cytochrome c release, and caspase-9 and -3 activation in this paradigm.
The human glioblastoma cell lines, U87MG, A172 and U118MG express the MPTP-associated TSPO, voltage-dependent anion channel and adenine nucleotide transporter. Indeed, ErPC3-induced apoptosis was inhibited by the MPTP blocker cyclosporin A and by PK 11195 and Ro5 4864 in a concentration-dependent manner. Furthermore, PK 11195 and Ro5 4864 inhibited collapse of the mitochondrial membrane potential, cytochrome c release, and caspase-9 and -3 activation caused by ErPC3 treatment.
This study shows that PK 11195 and Ro5 4864 inhibit the pro-apoptotic function of ErPC3 by blocking its capacity to cause a collapse of the mitochondrial membrane potential. Thus, the TSPO may serve to open the MPTP in response to anti-cancer drugs such as ErPC3.