Abstract |
Ceramide is a sphingolipid that activates stress kinases such as p38 and c-JUN N-Terminal Kinase (JNK). Though Chronic Myelogenous Leukemia (CML) derived K562 cells resist killing by short chain C2-ceramide, we report here that longer chain C6-ceramide promotes apoptosis in these cells. C6-ceramide induces cleavage of Caspase-8 and Caspase-9, but only Caspase-8 is required for apoptosis. The sphingolipid killed CML derived KBM5 cells and, to a lesser extent, imatinib-resistant KBM5-STI cells suggesting that BCR-ABL can not completely block C6-ceramide-induced apoptosis but the kinase may regulate the process. BCR-ABL is known to suppress Protein Phosphatase 2A (PP2A) in CML cells. While C6-ceramide can activate PP2A in acute leukemia cells, the sphingolipid did not activate the phosphatase in K562 cells. C6-ceramide did not activate p38 kinase but did promote JNK activation and phosphorylation of JUN. Inhibition of JNK by pharmacological agent protected K562 cells from C6-ceramide suggesting that JNK plays an essential role in C6-ceramide mediated apoptosis. Furthermore, the sphingolipid promoted MCL-1 phosphorylation by a mechanism that, at least in part, involves JNK. The findings presented here suggest that Caspase-8, JNK, and perhaps MCL-1 may play important roles in regulating cell death and may represent new targets for therapeutic strategies for CML.
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Authors | Alina Felicia Nica, Chun Chui Tsao, Julie C Watt, Tilahun Jiffar, Svitlana Kurinna, Paul Jurasz, Marina Konopleva, Michael Andreeff, Marek W Radomski, Peter P Ruvolo |
Journal | Cell cycle (Georgetown, Tex.)
(Cell Cycle)
Vol. 7
Issue 21
Pg. 3362-70
(Nov 01 2008)
ISSN: 1551-4005 [Electronic] United States |
PMID | 18948750
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Benzamides
- Ceramides
- Myeloid Cell Leukemia Sequence 1 Protein
- Piperazines
- Protein Kinase Inhibitors
- Proto-Oncogene Proteins c-bcl-2
- Pyrimidines
- Imatinib Mesylate
- Fusion Proteins, bcr-abl
- Extracellular Signal-Regulated MAP Kinases
- JNK Mitogen-Activated Protein Kinases
- p38 Mitogen-Activated Protein Kinases
- Protein Phosphatase 2
- Caspase 8
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Topics |
- Apoptosis
(drug effects)
- Benzamides
- Caspase 8
(metabolism)
- Ceramides
(pharmacology)
- Drug Resistance, Neoplasm
(drug effects)
- Enzyme Activation
(drug effects)
- Extracellular Signal-Regulated MAP Kinases
(metabolism)
- Fusion Proteins, bcr-abl
(metabolism)
- Humans
- Imatinib Mesylate
- JNK Mitogen-Activated Protein Kinases
(antagonists & inhibitors, metabolism)
- K562 Cells
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
(enzymology, pathology)
- Myeloid Cell Leukemia Sequence 1 Protein
- Phosphorylation
(drug effects)
- Piperazines
(pharmacology)
- Protein Kinase Inhibitors
(pharmacology)
- Protein Phosphatase 2
(metabolism)
- Proto-Oncogene Proteins c-bcl-2
(metabolism)
- Pyrimidines
(pharmacology)
- p38 Mitogen-Activated Protein Kinases
(metabolism)
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