Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells.
The sphingolipid ceramide has been recognized as an important second messenger implicated in regulating diverse signaling pathways especially for apoptosis. Very little is known, however, about the molecular mechanisms underlying nonapoptotic cell death induced by ceramide. In the present study, we first demonstrate that ceramide induces nonapoptotic cell death in malignant glioma cells. The cell death was accompanied by several specific features characteristic of autophagy: presence of numerous autophagic vacuoles in the cytoplasm, development of the acidic vesicular organelles, autophagosome membrane association of microtubule-associated protein light chain 3 (LC3), and a marked increase in expression levels of two forms of LC3 protein (LC3-I and LC3-II). We additionally demonstrate that ceramide decreases mitochondrial membrane potential and activates the transcription of death-inducing mitochondrial protein, BNIP3, resulting in increased expression levels of its mRNA and protein in malignant glioma cells. Moreover, tumor cells transfected with BNIP3 gene undergo autophagy in the absence of ceramide. These results suggest that ceramide induces autophagic cell death in malignant glioma cells via activation of BNIP3. This study adds a new concept to characterize the pathways by which ceramide acts to induce nonapoptotic autophagic cell death in malignant gliomas.
Daido
Shigeru
S
Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, USA.
Kanzawa
Takao
T
Yamamoto
Akitsugu
A
Takeuchi
Hayato
H
Kondo
Yasuko
Y
Kondo
Seiji
S
D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014162:Transfection
C090121:BNIP3 protein, human; D008565:Membrane Proteins; C064769:N-acetylsphingosine; D011518:Proto-Oncogene Proteins; D013110:Sphingosine