Ceramide promotes apoptosis in chronic myelogenous leukemia-derived K562 cells by a mechanism involving caspase-8 and JNK.

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.

• 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)

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

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)