Alkylphosphocholine-induced glioma cell death is BCL-X(L)-sensitive, caspase-independent and characterized by massive cytoplasmic vacuole formation

U Naumann; J Wischhusen; S Weit; J Rieger; H Wolburg; U Massing; M Weller

doi:10.1038/sj.cdd.4401503

Alkylphosphocholine-induced glioma cell death is BCL-X(L)-sensitive, caspase-independent and characterized by massive cytoplasmic vacuole formation

Cell Death Differ. 2004 Dec;11(12):1326-41. doi: 10.1038/sj.cdd.4401503.

Authors

U Naumann¹, J Wischhusen, S Weit, J Rieger, H Wolburg, U Massing, M Weller

Affiliation

¹ Laboratory of Molecular Neuro-Oncology, Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. [email protected]

PMID: 15389288
DOI: 10.1038/sj.cdd.4401503

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / toxicity*
Apoptosis / drug effects*
Apoptosis / physiology
Astrocytes / drug effects
Brain Neoplasms / drug therapy*
Brain Neoplasms / pathology
Brain Neoplasms / ultrastructure
Caspases / drug effects
Caspases / metabolism*
Cell Line, Tumor
Collagen Type XI / drug effects
Collagen Type XI / metabolism
Cytoplasm / drug effects
Cytoplasm / pathology
Cytoplasm / ultrastructure
Free Radicals / metabolism
Glioma / drug therapy*
Glioma / pathology
Glioma / ultrastructure
Humans
Membrane Potentials / drug effects
Membrane Potentials / genetics
Microscopy, Electron, Transmission
Mitochondria / drug effects
Mitochondria / metabolism
Phosphorylcholine / analogs & derivatives*
Phosphorylcholine / toxicity*
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases
Proteins / genetics
Proto-Oncogene Proteins c-bcl-2 / drug effects
Proto-Oncogene Proteins c-bcl-2 / metabolism*
Signal Transduction / drug effects
Signal Transduction / physiology
Stearates / toxicity
Vacuoles / drug effects
Vacuoles / pathology
Vacuoles / ultrastructure
X-Linked Inhibitor of Apoptosis Protein
bcl-X Protein

Substances

1-O-phosphocholine-2-O-acetyloctadecane
1-O-phosphocholine-2-O-methyloctadecane
Antineoplastic Agents
BCL2L1 protein, human
COL11A2 protein, human
Collagen Type XI
Free Radicals
Proteins
Proto-Oncogene Proteins c-bcl-2
Stearates
X-Linked Inhibitor of Apoptosis Protein
XIAP protein, human
bcl-X Protein
Phosphorylcholine
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases
Caspases