Secretory phospholipase A2 induces apoptosis via a mechanism involving ceramide generation

Zhao, Sheng; Du, Xiaoyan; Chai, Min-Qiang; Chen, Jun‐Song; Zhou, Yuan-Chong; Song, Jianguo

doi:10.1016/s1388-1981(02)00122-1

Cited by 26 publications

(17 citation statements)

References 39 publications

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“…In various cell culture systems, cPLA 2 activity has been directly associated with apoptosis (25,49,50). To determine whether such an association occurs in vivo, we evaluated the frequency of apoptotic cells within the colonic epithelium of each genotype, using the TUNEL assay.…”

Section: Resultsmentioning

confidence: 99%

Cytoplasmic Phospholipase A2 Deletion Enhances Colon Tumorigenesis

Ilsley

Nakanishi²,

Flynn³

et al. 2005

Cancer Research

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Cellular pools of free arachidonic acid are tightly controlled through enzymatic release of the fatty acid and subsequent utilization by downstream enzymes including the cyclooxygenases. Arachidonic acid cleavage from membrane phospholipids is accomplished by the actions of phospholipase A 2 (PLA 2 ). Upon release, free arachidonic acid provides substrate for the synthesis of eicosanoids. However, under certain conditions, arachidonic acid may participate in ceramidemediated apoptosis. Disruption of arachidonic acid homeostasis can shift the balance of cell turnover in favor of tumorigenesis, via overproduction of tumor-promoting eicosanoids or alternatively by limiting proapoptotic signals. In the following study, we evaluated the influence of genetic deletion of a key intracellular phospholipase, cytoplasmic PLA 2 (cPLA 2 ), on azoxymethane-induced colon tumorigenesis. Heterozygous and null mice, upon treatment with the organotropic colon carcinogen, azoxymethane, developed a significant (P < 0.05) increase in colon tumor multiplicity (7.2-fold and 5.5-fold, respectively) relative to their wild-type littermates. This enhanced tumor sensitivity may be explained, in part, by the attenuated levels of apoptosis observed by terminal deoxynucleotidyl transferase-mediated nick end labeling staining within the colonic epithelium of heterozygous and null mice (% % %50% of wild type). The lower frequency of apoptotic cells corresponded with reduced ceramide levels (69% and 46% of wild-type littermates, respectively). Remarkably, increased tumorigenesis resulting from cPLA 2 deletion occurred despite a significant reduction in prostaglandin E 2 production, even in cyclooxygenase-2-overexpressing tumors. These data contribute new information that supports a fundamental role of cPLA 2 in the control of arachidonic acid homeostasis and cell turnover. Our findings indicate that the proapoptotic role of cPLA 2 in the colon may supercede its contribution to eicosanoid production in tumor development.

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Section: Resultsmentioning

confidence: 99%

Cytoplasmic Phospholipase A2 Deletion Enhances Colon Tumorigenesis

Ilsley

Nakanishi²,

Flynn³

et al. 2005

Cancer Research

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“…Some of the suggested effectors include ceramide-activated protein kinases such as p42/p44 mitogen-activated protein kinase and c-Jun N-terminal-directed protein kinase [36] as well as ceramide-activated protein phosphatases [16,37,38] and caspases [16]. Sphingomyelin degradation by sphingomyelinase action is followed by secretory PLA2 activation in MV1Lu cells [39], and PLA 2 has also been suggested as a target of ceramide [37,40]. The ceramide effectors mediating acrosomal exocytosis have not yet been investigated.…”

Section: Discussionmentioning

confidence: 99%

Ceramide Enhances Acrosomal Exocytosis Triggered by Calcium and the Calcium Ionophore A23187 in Boar Spermatozoa

Murase

Imaeda

Kondoh

et al. 2004

Journal of Reproduction and Development

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Abstract. Mammalian spermatozoa must undergo acrosomal exocytosis prior to penetration of the oocyte at fertilization. The mechanisms underlying acrosomal exocytosis have not yet been fully elucidated. This study explored the possible involvement of ceramide in exocytosis of the boar sperm acrosome. Ejaculated boar spermatozoa, stored with the Beltsville TS extender at 17C for up to 3 days, were washed and preincubated for 10 min with C2-ceramide, an analogue of endogenous ceramide, C2-dihydroceramide (C2-DH-ceramide), a negative control to C2-ceramide, or with (1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol (D-erythro-MAPP), an inhibitor of alkaline ceramidase, followed by incubation and stimulation with 3 mM Ca 2+ and 0.3 µM A23187 (Ca 2+ /A23187) at 37C in air in a water bath. Spermatozoa fixed at specific intervals were examined, and the % of acrosomal exocytosis was monitored. Stimulation of spermatozoa with Ca 2+ /A23187 resulted in a timedependent increase. There were no obvious changes at 5 min, but this was followed by a rapid increase at 10 min, reaching nearly a maximum level after 15 min or more of incubation. Preincubation with C2-ceramide or D-erythro-MAPP enhanced acrosomal exocytosis triggered by Ca 2+ /A23187 in a dose-dependent manner, whereas C2-DH-ceramide was without effect. These results suggest the possibility that ceramide may be involved in the mechanisms underlying acrosomal exocytosis.

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“…38 Briefly, cells cultured in 60-mm plates were lysed in the following buffers, respectively: (1) neutral Mg 2+ -dependent: 0.1% Triton X-100, 5 mM MgCl 2 , and 20 mM HEPES (pH 7.4); (2) neutral Mg 2+ -independent: 0.1% Triton X-100 and 20 mM HEPES (pH 7.4); (3) acidic: 0.1% Triton X-100 and 0.1 M sodium acetate (pH 5.0). The lysates were centrifuged at 12 000 g for 10 min.…”

Section: Smase Activity Assaymentioning

confidence: 99%

TGF-β1 suppresses apoptosis via differential regulation of MAP kinases and ceramide production

2003

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Serum deprivation induces apoptosis in NIH3T3 cells, which is associated with increased intracellular ceramide generation and with the activation of p38 mitogen-activated protein (MAP) kinase. Treatment of cells with transforming growth factor-b1 (TGF-b1) activated the extracellular signal regulated kinases 1 and 2 (ERK1/ERK2), inhibited the serum deprivation-induced p38 activation and the increase in intracellular ceramide formation, leading to the stimulation of cell proliferation and the suppression of apoptosis. Inhibition of p38 MAP kinase by SB203580 significantly reduced the serum-deprivation-induced apoptosis. Overexpression of p38 increased the cell apoptosis and reduced the antiapoptotic effect of TGF-b1. Inhibition of ERK1/ERK2 by PD98059 completely inhibited the TGF-b1-stimulated proliferation and partially inhibited the antiapoptotic effects of TGF-b1. Neither SB203580 nor PD98059 has obvious effect on TGF-b1-mediated inhibition of the increased ceramide generation. Serum-deprivation-induced apoptosis in NIH3T3 cells can also be blocked by broad-spectrum caspase inhibitor. TGF-b1 treatment has an inhibitory effect on caspase activities. Our results indicate that ceramide, p38, and ERK1/ERK2 play critical but differential roles in cell proliferation and stressinduced apoptosis. TGF-b1 suppresses the serum-deprivation-induced apoptosis via its distinct effects on complex signaling events involving the activation of ERK1/ERK2 and the inhibition of p38 activation and increased ceramide generation.

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Secretory phospholipase A2 induces apoptosis via a mechanism involving ceramide generation

Cited by 26 publications

References 39 publications

Cytoplasmic Phospholipase A2 Deletion Enhances Colon Tumorigenesis

Cytoplasmic Phospholipase A2 Deletion Enhances Colon Tumorigenesis

Ceramide Enhances Acrosomal Exocytosis Triggered by Calcium and the Calcium Ionophore A23187 in Boar Spermatozoa

TGF-β1 suppresses apoptosis via differential regulation of MAP kinases and ceramide production

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