Cytoplasmic condensation is both necessary and sufficient to induce apoptotic cell death.
Programmed cell death (apoptosis) is important in tissue maintenance. Hallmarks of apoptosis include caspase activation, DNA fragmentation and an overall reduction in cell volume. Whether this apoptotic volume decrease (AVD) is a mere response to initiators of apoptosis or whether it is functionally significant is not clear. In this study, we sought to answer this question using human malignant glioma cells as a model system. In vivo, high grade gliomas demonstrate an increased percentage of apoptotic cells as well as upregulation of death ligand receptors. By dynamically monitoring cell volume, we show that the induction of apoptosis, via activation of either the intrinsic or extrinsic pathways with staurosporine or TRAIL, respectively, resulted in a rapid AVD in D54-MG human glioma cells. This decrease in cell volume could be prevented by inhibiting the efflux of Cl(-) through channels. Such suppression of AVD also reduced the activation of caspases 3, 8 and 9 and suppressed DNA fragmentation. Importantly, experimental manipulations that reduce the cell volume to 70% of the original volume for periods of at least 3 hours were sufficient to initiate apoptosis even in the absence of death ligands. Hence, this data suggests that cell condensation is both necessary and sufficient for the induction of apoptosis.
Ernest
Nola Jean
NJ
Department of Neurobiology, Civitan International Research Center, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Habela
Christa W
CW
Sontheimer
Harald
H
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D048429:Cell Size / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000473:pathology*; D053938:DNA Fragmentation / Q000187:drug effects; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D008954:Models, Biological; D011994:Recombinant Proteins / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology
D002712:Chlorides; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D020169:Caspases; D019311:Staurosporine; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid