Involvement of mitochondrial aggregation in arsenic trioxide (As2O3)-induced apoptosis in human glioblastoma cells.
Arsenic trioxide (As(2)O(3)) is effective against acute promyelocytic leukemia and has potential as a novel treatment against malignant solid tumors. As(2)O(3) induces differentiation and inhibits growth. It also causes mitochondrial damage mediated by the production of reactive oxygen species (ROS) and the dissipation of mitochondrial transmembrane potential (DeltaPsi(m)), leading to apoptosis. Mitochondria might be the key target of antitumor activity by As(2)O(3); however, its mechanisms have not been completely elucidated. Using two human glioblastoma cell lines, A172 and T98G, we found that As(2)O(3) induced apoptosis in A172 cells but not in T98G cells. As(2)O(3)-induced ROS production was observed in both cell lines; however, the dissipation of DeltaPsi(m), Bax oligomerization and caspase activation occurred only in As(2)O(3)-sensitive A172 cells. To determine the mechanisms of As(2)O(3)-induced apoptosis after ROS generation, we examined the change of mitochondrial morphology. As we reported previously, mitochondrial aggregation occurs before cytochrome c release during apoptosis, thus playing a role in cell death progression. We observed mitochondrial aggregation in As(2)O(3)-sensitive A172 cells but not in T98G cells treated with As(2)O(3). Using laser scanning cytometry, we quantitatively confirmed the results, which indicate that mitochondrial aggregation plays an important role in regulating sensitivity to As(2)O(3)-induced apoptosis. We propose a sequential process involving ROS generation, mitochondrial aggregation, Bax oligomerization and DeltaPsi(m) dissipation, and caspase activation during As(2)O(3)-induced apoptosis.
Haga
Naomi
N
Institute of Molecular and Cellular Biosciences, The University of Tokyo, Japan.
Fujita
Naoya
N
Tsuruo
Takashi
T
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D010087:Oxides / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D020169:Caspases; D000077237:Arsenic Trioxide