Release of plasminogen activator inhibitor‐1 from human astrocytes is regulated by intracellular ceramide

Kimura, Masahiko; Soeda, Shinji; Oda, Masatoshi; Ochiai, Takashi; Kihara, Taro; Ono, Nobufumi; Shimeno, Hiroshi

doi:10.1002/1097-4547(20001215)62:6<781::aid-jnr4>3.3.co;2-n

Cited by 5 publications

(10 citation statements)

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“…The specific role of de novo synthesized ceramide in apoptosis, however, remains unknown. 9,24 Our findings suggest that the de novo synthesized ceramide in Sarcoma 180, B16 melanoma and Lewis lung carcinoma tumors may be linked to a survival signaling system related to cellular differentiation and proliferation.…”

Section: Discussionmentioning

confidence: 79%

Elevation of de novo ceramide synthesis in tumor masses and the role of microsomal dihydroceramide synthase

Koyanagi¹,

Kuga²,

Soeda³

et al. 2003

Intl Journal of Cancer

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Ceramide is formed through sphingomyelin hydrolysis or de novo synthesis and may play a key role in cell growth, differentiation and apoptosis. To clarify which pathway tumor cells use to form ceramide and how its formation is regulated, we determined the levels of dihydroceramide and ceramide in mice inoculated with Sarcoma 180, B16 melanoma or Lewis lung carcinoma cells. The levels in these tumor masses were very high compared to those in other healthy tissues. The high levels were significantly reduced by a single administration of the dihydroceramide synthase inhibitor fumonisin B 1 , but not by a sphingomyelinase inhibitor, sphingomyelin analog-1 (SMA-1), suggesting that the tumor cells have a very effective means of synthesizing dihydroceramide and ceramide. To investigate the characteristics of dihydroceramide synthase, we prepared microsomes from Sarcoma 180 tumor masses and healthy mouse liver cells, and compared their catalytic activities on dihydroceramide formation. A kinetic analysis using sphinganine and palmitoyl CoA as substrates revealed that the enzyme present in the tumor formed dihydroceramide 3 times more efficiently than that in healthy liver cells. Partial purification of dihydroceramide synthase from bovine liver microsomes revealed that the enzyme was present in healthy tissues as a 333 kDa form constructed of 47 kDa subunit proteins. However, gel filtration of the enzyme solubilized from the Sarcoma 180 tumor masses demonstrated that its molecular weight was 1,300 kDa. These results suggest that malignant transformation causes the cell to produce a form of dihydroceramide synthase with a larger than normal molecular mass; the increased molecular mass may account for the enzyme's increased catalytic efficiency. Ceramide has received much attention recently as an important mediator in regulating a cell's response to stress. Inducers of ceramide formation include tumor necrosis factor-␣, interleukin 1␤, Fas ligand, and 1,25-dihydroxy vitamin D 3 . 1 Many of these agents produce ceramide through hydrolysis of sphingomyelin (SM) after the activation of sphingomyelinase (SMase). Studies using fungal metabolites, fumonisins, demonstrated, howeves, that ceramide formed through the de novo synthesis pathway is also implicated in apoptosis. 2,3 Fumonisin inhibits the activity of dihydroceramide synthase, 4,5 an enzyme in the de novo pathway that catalyzes N-acetylation of sphinganine to produce dihydroceramide. The conversion of dihydroceramide to ceramide is catalyzed by a desaturase present in microsomes. 6 Several chemotherapeutic agents, such as daunorubicin, 2 etoposide, 7 and hexadecylphosphocholine, 8 have been reported to induce de novo ceramide formation during apoptosis of tumor cells. These findings suggest that tumor cells may synthesize ceramide in amounts close to or under normal levels because the cells need to lengthen their lifespan by holding the apoptotic effects of ceramide to a minimum. Little is known, however, about the correlation between ceramide levels and tumor survival...

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Section: Discussionmentioning

confidence: 79%

Elevation of de novo ceramide synthesis in tumor masses and the role of microsomal dihydroceramide synthase

Koyanagi¹,

Kuga²,

Soeda³

et al. 2003

Intl Journal of Cancer

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“…It also actively induces proliferative signalling cascades; for example, the Stat3 pathway 17. The main inhibitor of uPA, PAI‐1, could be shown to be a lot more than just that; it also has effects on cell adhesion and modulates intracellular signalling, primarily through up‐regulation of apoptotic pathways 18–21.…”

Section: Introductionmentioning

confidence: 99%

Signalling networks associated with urokinase‐type plasminogen activator (uPA) and its inhibitor PAI‐1 in breast cancer tissues: new insights from protein microarray analysis

Wolff

Malinowsky

Berg

et al. 2010

The Journal of Pathology

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The urokinase-type plasminogen activator (uPA) and the main uPA inhibitor PAI-1 play important roles in cell migration and invasion in both physiological and pathological contexts. Both factors are clinically applicable predictive markers in node-negative breast cancer patients that are used to stratify patients for adjuvant chemotherapy. In addition to their classical functions in plasmin regulation, both factors are key components in cancer-related cell signalling. Such signalling cascades are well described in cell culture systems, but a better understanding of uPA- and PAI-1-associated signalling networks in clinical tissues is needed. We examined the expression of uPA, PAI-1, and 21 signalling molecules in 201 primary breast cancer tissues using protein microarrays. Expression of uPA was significantly correlated with the expression of ERK and Stat3, while expression of PAI-1 was correlated with the uPA receptor and Akt activation, presumably via integrin and HER-receptor signalling. Analysis of uPA expression did not reveal any significant correlation with staging, grading or age of the patients. The PAI-1 expression was correlated with nodal stage. Network monitoring for uPA and PAI-1 in breast cancer reveals interactions with main signalling cascades and extends the findings from cell culture experiments. Our results reveal possible mechanisms underlying cancer development.

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“…Astrocytes express both t‐PA and one of its inhibitors, plasminogen activator inhibitor type 1 (PAI‐1) [14]. Previous studies have focused on the regulation of PAI‐1.…”

Section: Introductionmentioning

confidence: 99%

Retinoids and activation of PKC induce tissue‐type plasminogen activator expression and storage in human astrocytes

Hultman

Tjärnlund-Wolf

Fish

et al. 2008

Journal of Thrombosis and Haemostasis

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PKC induce tissue-type plasminogen activator expression and storage in human astrocytes. J Thromb Haemost 2008; 6: 1796-803. Summary.Background: Emerging data demonstrate important roles for tissue-type plasminogen activator (t-PA) in the central nervous system (CNS). In contrast to endothelial cells, little is known about the regulation of t-PA gene expression and secretion in astrocytes. Objectives: The aims of the present study were to investigate whether t-PA gene expression is regulated by retinoids and the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) in human astrocytes, and to study whether t-PA is stored and subject to regulated release from these cells, as with endothelial cells. Methods: Native human astrocytes were treated with RA and/or PMA. mRNA was quantified by real-time RT-PCR and protein secretion determined by ELISA. Intracellular t-PA immunoreactivity in astrocytes was examined by immunocyto-and histochemistry. Results: RA and/or PMA induced a time-dependent increase in t-PA mRNA and protein levels in astrocytes, reaching 10-fold after combined treatment. This was associated with increased amounts of t-PA storage in intracellular granular structures. Both forskolin and histamine induced regulated release of t-PA. The presence of t-PA in reactive astrocytes was confirmed in human brain tissue. Conclusions: These data show that RA and PKC activation induce a strong up-regulation of t-PA expression in astrocytes, and increased intracellular storage pools. Moreover, a regulated release of t-PA can be induced from these cells. This raises the possibility that astrocytes contribute to the regulation of extracellular t-PA levels in the CNS.

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Release of plasminogen activator inhibitor‐1 from human astrocytes is regulated by intracellular ceramide

Cited by 5 publications

References 0 publications

Elevation of de novo ceramide synthesis in tumor masses and the role of microsomal dihydroceramide synthase

Elevation of de novo ceramide synthesis in tumor masses and the role of microsomal dihydroceramide synthase

Signalling networks associated with urokinase‐type plasminogen activator (uPA) and its inhibitor PAI‐1 in breast cancer tissues: new insights from protein microarray analysis

Retinoids and activation of PKC induce tissue‐type plasminogen activator expression and storage in human astrocytes

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