title: Potential involvement of F0F1-ATP(synth)ase and reactive oxygen species in apoptosis induction by the antineoplastic agent erucylphosphohomocholine in glioblastoma cell lines : a mechanism for induction of apoptosis via the 18 kDa mitochondrial translocator protein.
abstract: Erucylphosphohomocholine (ErPC3, Erufosine) was reported previously to induce apoptosis in otherwise highly apoptosis-resistant malignant glioma cell lines while sparing their non-tumorigenic counterparts. We also previously found that the mitochondrial 18 kDa Translocator Protein (TSPO) is required for apoptosis induction by ErPC3. These previous studies also suggested involvement of reactive oxygen species (ROS). In the present study we further investigated the potential involvement of ROS generation, the participation of the mitochondrial respiration chain, and the role of the mitochondrial F(O)F(1)-ATP(synth)ase in the pro-apoptotic effects of ErPC3 on U87MG and U118MG human glioblastoma cell lines. For this purpose, cells were treated with the ROS chelator butylated hydroxyanisole (BHA), the mitochondrial respiration chain inhibitors rotenone, antimycin A, myxothiazol, and the uncoupler CCCP. Also oligomycin and piceatannol were studied as inhibitors of the F(O) and F(1) subunits of the mitochondrial F(O)F(1)-ATP(synth)ase, respectively. BHA was able to attenuate apoptosis induction by ErPC3, including mitochondrial ROS generation as determined with cardiolipin oxidation, as well as collapse of the mitochondrial membrane potential (Deltapsi(m)). Similarly, we found that oligomycin attenuated apoptosis and collapse of the Deltapsi(m), normally induced by ErPC3, including the accompanying reductions in cellular ATP levels. Other inhibitors of the mitochondrial respiration chain, as well as piceatannol, did not show such effects. Consequently, our findings strongly point to a role for the F(O) subunit of the mitochondrial F(O)F(1)-ATP(synth)ase in ErPC3-induced apoptosis and dissipation of Deltapsi(m) as well as ROS generation by ErPC3 and TSPO.
authors.affiliation: Department of Molecular Pharmacology, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, P.O. Box 9649, Bat-Galim, 31096, Haifa, Israel. veenmanl@techunix.technion.ac.il
authors.forename: Leo
authors.initials: L
authors.lastname: Veenman
authors.forename: Julia
authors.initials: J
authors.lastname: Alten
authors.forename: Karen
authors.initials: K
authors.lastname: Linnemannstöns
authors.forename: Yulia
authors.initials: Y
authors.lastname: Shandalov
authors.forename: Sivan
authors.initials: S
authors.lastname: Zeno
authors.forename: Max
authors.initials: M
authors.lastname: Lakomek
authors.forename: Moshe
authors.initials: M
authors.lastname: Gavish
authors.forename: Wilfried
authors.initials: W
authors.lastname: Kugler
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism*; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004883:Erucic Acids / Q000633:toxicity*; D005909:Glioblastoma / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors; D000083162:Mitochondrial Permeability Transition Pore; D009840:Oligomycins / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000633:toxicity; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018079:Receptors, GABA / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004883:Erucic Acids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009840:Oligomycins; D017382:Reactive Oxygen Species; D018079:Receptors, GABA; D013267:Stilbenes; C499229:TSPO protein, human; C518520:erucylphosphohomocholine ErPC3; D010767:Phosphorylcholine; D002083:Butylated Hydroxyanisole; C041525:3,3',4,5'-tetrahydroxystilbene; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D020169:Caspases; D006180:Proton-Translocating ATPases