Open AccessLigands of the Mitochondrial 18 kDa Translocator Protein Attenuate Apoptosis of Human Glioblastoma Cells Exposed to Erucylphosphohomocholine
Author(s) -
Wilfried Kugler,
Leo Veenman,
Yulia Shandalov,
Svetlana Leschiner,
Ilana Spanier,
M. Lakomek,
Moshe Gavish
Publication year - 2008
Publication title -
analytical cellular pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.576
H-Index - 24
eISSN - 2210-7185
pISSN - 2210-7177
DOI - 10.1155/2008/235368
Subject(s) - translocator protein , mitochondrial permeability transition pore , mptp , apoptosis , cytochrome c , adenine nucleotide translocator , mitochondrion , programmed cell death , microbiology and biotechnology , inner mitochondrial membrane , biology , chemistry , cancer research , pharmacology , biochemistry , neuroscience , immunology , inflammation , dopaminergic , dopamine , neuroinflammation
Background : 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. Methods : 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. Results : 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. Conclusions : 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.