Stress-Induced Sphingolipid Signaling: Role of Type-2 Neutral Sphingomyelinase in Murine Cell Apoptosis and Proliferation

Devillard, Raphaël; Galvani, Sylvain; Thiers, Jean-Claude; Guénet, Jean-Louis; Hannun, Yusuf A.; Bielawski, Jacek; Nègre‐Salvayre, Anne; Salvayre, Robert; Augé, Nathalie

doi:10.1371/journal.pone.0009826

Cited by 25 publications

(25 citation statements)

References 43 publications

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“…Consistent with this dual role of ceramide, it has been recently shown in vitro that nSMase2 function and subsequent ceramide generation under TNF-a-or oxidized lowdensity lipoprotein-induced cell stress can be mechanistically linked to both apoptosis initiation and cell proliferation (47). An additional recent publication claims that the loss of ceramide transfer protein (CERT) augments EGFR signaling in breast cancer via its regulation of a cellular pool of sphingomyelin (SM).…”

Section: F the Link Between Ceramide And Src Underlies Their Dual Romentioning

confidence: 90%

Lung Injury and Lung Cancer Caused by Cigarette Smoke-Induced Oxidative Stress: Molecular Mechanisms and Therapeutic Opportunities Involving the Ceramide-Generating Machinery and Epidermal Growth Factor Receptor

Goldkorn

Filosto

Chung

2014

Antioxidants & Redox Signaling

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Chronic obstructive pulmonary disease (COPD) and lung cancer are frequently caused by tobacco smoking. However, these diseases present opposite phenotypes involving redox signaling at the cellular level. While COPD is characterized by excessive airway epithelial cell death and lung injury, lung cancer is caused by uncontrolled epithelial cell proliferation. Notably, epidemiological studies have demonstrated that lung cancer incidence is significantly higher in patients who have preexisting emphysema/lung injury. However, the molecular link and common cell signaling events underlying lung injury diseases and lung cancer are poorly understood. This review focuses on studies of molecular mechanism(s) underlying smoking-related lung injury (COPD) and lung cancer. Specifically, the role of the ceramide-generating machinery during cigarette smoke-induced oxidative stress leading to both apoptosis and proliferation of lung epithelial cells is emphasized. Over recent years, it has been established that ceramide is a sphingolipid playing a major role in lung epithelia structure/function leading to lung injury in chronic pulmonary diseases. However, new and unexpected findings draw attention to its potential role in lung development, cell proliferation, and tumorigenesis. To address this dichotomy in detail, evidence is presented regarding several protein targets, including Src, p38 mitogen-activated protein kinase, and neutral sphingomyelinase 2, the major sphingomyelinase that controls ceramide generation during oxidative stress. Furthermore, their roles are presented not only in apoptosis and lung injury but also in enhancing cell proliferation, lung cancer development, and resistance to epidermal growth factor receptor-targeted therapy for treating lung cancer.

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Section: F the Link Between Ceramide And Src Underlies Their Dual Romentioning

confidence: 90%

Lung Injury and Lung Cancer Caused by Cigarette Smoke-Induced Oxidative Stress: Molecular Mechanisms and Therapeutic Opportunities Involving the Ceramide-Generating Machinery and Epidermal Growth Factor Receptor

Goldkorn

Filosto

Chung

2014

Antioxidants & Redox Signaling

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“…Several biological responses are associated with nSMase activation, including inflammation, atherogenesis, and apoptosis. 24,25 Two forms of mammalian nSMase have been identified, namely nSMase1 and nSMase2.…”

Section: Discussionmentioning

confidence: 99%

Platelet protease-activated receptor (PAR)4, but not PAR1, associated with neutral sphingomyelinase responsible for thrombin-stimulated ceramide-NF- B signaling in human platelets

et al. 2012

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Thrombin activates platelets mainly through protease-activated receptor (PAR)1 and PAR4. However, downstream platelet signaling between PAR1 and PAR4 is not yet well understood. This study investigated the relationship between nSMase/ceramide and the NF-κB signaling pathway in PARs-mediated human platelet activation. The LC-MS/MS, aggregometry, flow cytometry, immunoprecipitation, and mesenteric microvessels of mice were used in this study. Human platelets stimulated by thrombin, 3-OMS (a neutral sphingomyelinase [nSMase] inhibitor) and Bay11-7082 (an NF-κB inhibitor) significantly inhibited platelet activation such as P-selectin expression. Thrombin also activated IκB kinase (IKK)β and IκBα phosphorylation; such phosphorylation was inhibited by 3-OMS and SB203580 (a p38 MAPK inhibitor). Moreover, 3-OMS abolished platelet aggregation, IKKβ, and p38 MAPK phosphorylation stimulated by PAR4-AP (a PAR4 agonist) but not by PAR1-AP (a PAR1 agonist). Immunoprecipitation revealed that nSMase was directly associated with PAR4 but not PAR1 in resting platelets. In human platelets, C24:0-ceramide is the predominant form of ceramides in the LC/MS-MS assay; C24:0-ceramide increases after stimulation by thrombin or PAR4-AP, but not after stimulation by PAR1-AP. We also found that C2-ceramide (a cell-permeable ceramide analog) activated p38 MAPK and IKKβ phosphorylation in platelets and markedly shortened the occlusion time of platelet plug formation in vivo. This study demonstrated that thrombin activated nSMase by binding to PAR4, but not to PAR1, to increase the C24:0-ceramide level, followed by the activation of p38 MAPK-NF-κB signaling. Our results showed a novel physiological significance of PAR4-nSMase/ceramide-p38 MAPK-NF-κB cascade in platelet activation.

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“…Furthermore, apoptotic induction by ceramides is a known mechanism for stress-induced cell death as shown by numerous studies [51][52][53][54]. As an example, conversion of sphingomyelin to ceramide was documented during apoptosis upon heat-stress [55].…”

Section: Dihydrosphingosinementioning

confidence: 97%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

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Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.

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Stress-Induced Sphingolipid Signaling: Role of Type-2 Neutral Sphingomyelinase in Murine Cell Apoptosis and Proliferation

Cited by 25 publications

References 43 publications

Lung Injury and Lung Cancer Caused by Cigarette Smoke-Induced Oxidative Stress: Molecular Mechanisms and Therapeutic Opportunities Involving the Ceramide-Generating Machinery and Epidermal Growth Factor Receptor

Lung Injury and Lung Cancer Caused by Cigarette Smoke-Induced Oxidative Stress: Molecular Mechanisms and Therapeutic Opportunities Involving the Ceramide-Generating Machinery and Epidermal Growth Factor Receptor

Platelet protease-activated receptor (PAR)4, but not PAR1, associated with neutral sphingomyelinase responsible for thrombin-stimulated ceramide-NF- B signaling in human platelets

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

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