Akt protein kinase inhibits non-apoptotic programmed cell death induced by ceramide.
A growing body of evidence now suggests that programmed cell death (PCD) occurs via non-apoptotic mechanisms as well as by apoptosis. In contrast to apoptosis, however, the molecular mechanisms involved in the regulation of non-apoptotic PCD remain only poorly understood. Here we show that ceramide induces a non-apoptotic PCD with a necrotic-like morphology in human glioma cells. Characteristically, the cell death was not accompanied by loss of the mitochondrial transmembrane potential, cytosolic release of cytochrome c from mitochondria, or the activation of the caspase cascade. Consistent with these characteristics, this ceramide-induced cell death was inhibited neither by the overexpression of Bcl-xL nor by the pan-caspase inhibitor zVAD-fmk. However, strikingly, the ceramide-induced non-apoptotic cell death was inhibited by the activation of the Akt/protein kinase B pathway through the expression of a constitutively active version of Akt. The results for the first time indicate that the Akt kinase, known to play an essential role in survival factor-mediated inhibition of apoptotic cell death, is also involved in the regulation of non-apoptotic PCD.
Mochizuki
Toshihiro
T
Laboratory for Neuroscience and Neuro-oncology, Department of Neurosurgery, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Asai
Akio
A
Saito
Nobuhito
N
Tanaka
Sakae
S
Katagiri
Hideki
H
Asano
Tomoichiro
T
Nakane
Makoto
M
Tamura
Akira
A
Kuchino
Yoshiyuki
Y
Kitanaka
Chifumi
C
Kirino
Takaaki
T
D000256:Adenoviridae / Q000235:genetics; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002462:Cell Membrane / Q000201:enzymology; D002470:Cell Survival; D002518:Ceramides / Q000378:metabolism / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008564:Membrane Potentials; D008854:Microscopy, Electron; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
D000590:Amino Acid Chloromethyl Ketones; C494811:BCL2L1 protein, human; D002518:Ceramides; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases