Alkylphosphocholine-induced glioma cell death is BCL-X(L)-sensitive, caspase-independent and characterized by massive cytoplasmic vacuole formation.
Alkylphosphocholines (APC) are candidate anticancer agents. We here report that APC induce the formation of large vacuoles and typical features of apoptosis in human glioma cell lines, but not in immortalized astrocytes. APC promote caspase activation, poly(ADP-ribose)-polymerase (PARP) processing and cytochrome c release from mitochondria. Adenoviral X-linked inhibitor of apoptosis (XIAP) gene transfer, or exposure to the caspase inhibitor, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoro-methylketone zVAD-fmk, blocks caspase-7 and PARP processing, but not cell death, whereas BCL-X(L) blocks not only caspase-7 and PARP processing but also cell death. APC induce changes in Delta Psi m in sensitive glioma cells, but not in resistant astrocytes. The changes in Delta Psi m are unaffected by crm-A (cowpox serpin-cytokine response modifier protein A), XIAP or zVAD-fmk, but blocked by BCL-X(L), and are thus a strong predictor of cell death in response to APC. Free radicals are induced, but not responsible for cell death. APC thus induce a characteristic morphological, BCL-X(L)-sensitive, apparently caspase-independent cell death involving mitochondrial alterations selectively in neoplastic astrocytic cells.
Naumann
U
U
Laboratory of Molecular Neuro-Oncology, Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. ulrike.naumann@uni-tuebingen.de
Wischhusen
J
J
Weit
S
S
Rieger
J
J
Wolburg
H
H
Massing
U
U
Weller
M
M
D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D024161:Collagen Type XI / Q000187:drug effects / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D005609:Free Radicals / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000633:toxicity*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011506:Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013228:Stearates / Q000633:toxicity; D014617:Vacuoles / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein
C501218:1-O-phosphocholine-2-O-acetyloctadecane; C501219:1-O-phosphocholine-2-O-methyloctadecane; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C499319:COL11A2 protein, human; D024161:Collagen Type XI; D005609:Free Radicals; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013228:Stearates; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051020:bcl-X Protein; D010767:Phosphorylcholine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases