oligomycins and Glioblastoma

In glioblastoma multiforme (GBM), the activation of the phosphatidylinositol 3-kinase (PI3-K) pathway is known to promote aerobic glycolysis. The relative sensitivity of GBM towards PI3-K and metabolic inhibitors was examined in a panel of human GBM lines. We observed differential sensitivities towards oligomycin, an ATP synthase inhibitor that suppresses oxidative phosphorylation (OXPHOS). GBMs that were sensitive to oligomycin have greater intrinsic oxygen consumption. They also failed to undergo adaptive glycolytic switches in response to oligomycin, as reflected in the failure to activate AMPKα. On the other hand, GBM lines that were less sensitive to oligomycin could be rendered non-viable when simultaneously treated with the glycolysis inhibitor, 2-Deoxyglucose (2DG). Furthermore, inhibiting either PI3-K pathway or glycolysis was effective in suppressing cell migration. Inhibiting OXPHOS alone did not have any significant effects on cell motility. However, both oligomycin and 2DG acted synergistically in suppressing cell migration. We conclude that while there was less synergy by the combined inhibition of PI3-K and glycolysis, the simultaneous targeting of glycolysis and OXPHOS is highly effective in blocking GBM tumorigenic phenotypes.

Topics: Cell Differentiation; Cell Line, Tumor; Cell Movement; Cell Proliferation; Deoxyglucose; Glioblastoma; Humans; Oligomycins; Oxidative Phosphorylation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Signal Transduction

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.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Butylated Hydroxyanisole; Caspases; Cell Line, Tumor; Cyclosporine; Electron Transport; Enzyme Inhibitors; Erucic Acids; Glioblastoma; Humans; Membrane Potential, Mitochondrial; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Oligomycins; Phosphorylcholine; Proton-Translocating ATPases; Reactive Oxygen Species; Receptors, GABA; Stilbenes