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Implication of raft microdomains in drug induced apoptosis
Christine Bezombes1, Guy Laurent, Jean-Pierre Jaffrézou
1INSERM U563-CPTP, Institut Claudius Régaud, 20 rue du Pont St Pierre 31052, Toulouse, France.
Abstract:
DNA damaging agents such as 1-beta-D-arabinofuranosylcytosine (Ara-C) and daunorubicin (DNR) are widely used in the treatment of acute nonlymphocytic leukemia. These drugs have, of course, been the objects of intense basic research, as well as preclinical and clinical study. Although specific biochemical lesions (DNA damage) have been associated with Ara-C- and DNR-mediated cytotoxicity, the pathways leading to the induction of apoptosis remain ill defined. This standpoint has forced investigators to explore a new concept in cell response to cytotoxic stress: apoptosis signaling. The recent identification of a ceramide (CER) mediated apoptotic signaling pathway triggered by antitumor agents offers a new perspective for the treatment of neoplastic cells. Indeed, these agents have been shown to induce apoptosis through the activation of a sphingomyelinase (SMase) responsible for the hydrolysis of sphingomyelin (SM) and the generation of CER. The latter acts as a potent apoptosis mediator, triggering several downstream signaling pathways among which the stress-activated protein kinase cascade (MEKK1-SEK1-SAP/JNK) plays a critical role in apoptosis induction. However, the spacio-temporal organization of the key early signaling events is unclear. The present review delineates what appears to be a critical factor in apoptosis signaling: sphingomyelin enriched plasma membrane rafts. The apparent topological partitioning between DNA damage and apoptosis signaling (integrated into specialized plasma membrane domains) is discussed.
Insights
DNA damaging chemotherapy drugs induce apoptosis via ceramide signaling. This review explores how sphingomyelinase activation and ceramide generation in membrane rafts are key to this cell death pathway.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Chemotherapy drugs like 1-beta-D-arabinofuranosylcytosine (Ara-C) and daunorubicin (DNR) are used for acute nonlymphocytic leukemia.
- While DNA damage is known, the precise mechanisms of Ara-C and DNR-induced apoptosis are unclear.
- Apoptosis signaling pathways are a new focus for understanding cellular responses to cytotoxic stress.
Purpose of the Study:
- To review the role of ceramide (CER) in apoptosis signaling triggered by antitumor agents.
- To elucidate the spacio-temporal organization of early signaling events in apoptosis.
- To discuss the involvement of sphingomyelin-enriched plasma membrane rafts in integrating DNA damage and apoptosis signaling.
Main Methods:
- Review of existing literature on DNA damaging agents, apoptosis, and signaling pathways.
- Focus on the ceramide-mediated apoptotic pathway.
- Analysis of the role of sphingomyelinase (SMase) and ceramide generation.
Main Results:
- Antitumor agents can induce apoptosis via activation of sphingomyelinase (SMase).
- SMase hydrolyzes sphingomyelin (SM) to generate ceramide (CER), a potent apoptosis mediator.
- The stress-activated protein kinase cascade (MEKK1-SEK1-SAP/JNK) is critical for apoptosis induction downstream of ceramide.
Conclusions:
- Sphingomyelin-enriched plasma membrane rafts appear critical for apoptosis signaling.
- These specialized membrane domains may compartmentalize DNA damage and apoptosis signaling.
- Understanding these pathways offers new therapeutic perspectives for neoplastic cells.