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

• Published in: Cell cycle (Georgetown, Tex.) Vol. 7; no. 21; pp. 3362 - 3370
• Main Authors: Nica, Alina Felicia, Tsao, Chun Chui, Watt, Julie C., Jiffar, Tilahun, Kurinna, Svitlana, Jurasz, Paul, Konopleva, Marina, Andreeff, Michael, Radomski, Marek W., Ruvolo, Peter P.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01-11-2008
• Subjects: Apoptosis - drug effects; Benzamides; Binding; Biology; Bioscience; Calcium; Cancer; Caspase 8 - metabolism; Cell; Ceramides - pharmacology; Cycle; 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; JNK Mitogen-Activated Protein Kinases - metabolism; K562 Cells; Landes; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Myeloid Cell Leukemia Sequence 1 Protein; Organogenesis; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation - drug effects; Piperazines - pharmacology; Protein Kinase Inhibitors - pharmacology; Protein Phosphatase 2 - metabolism; Proteins; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pyrimidines - pharmacology
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.7.21.6894

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.