Platelet Activating Factor Inhibits the Expression of Matrix Metalloproteinases and Affects Invasiveness and Differentiation in a System of Human Neuroblastoma Clones

Barletta, Emanuela; Mugnai, Gabriele; Ruggieri, Salvatore

doi:10.1515/bc.2002.019

Cited by 7 publications

(7 citation statements)

References 33 publications

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“…The seemingly opposite effects of PAF on neuroblastoma and melanoma cells may be due to variations in PAF sensitivity. In the neuroblastoma cells, 300 nM PAF induced cell differentiation (67), whereas in our study, 100 nM PAF promoted cell growth in melanoma cells. In addition, the CREB and ATF-1 expression levels in different cell types may determine the ability of PAF to activate MMP-2.…”

Section: Discussioncontrasting

confidence: 77%

“…In these cells, MMP-2 activation occurred through a G␣ q protein-JAK-2-Src-mediated pathway (25,66). Negative regulation of MMPs by PAF has also been reported; Barletta et al (67) showed that 300 nM PAF down-regulated MT1-MMP and MMP-2 mRNA levels and reduced MMP-2 activation in isolated human neuroblastoma cell clones. The seemingly opposite effects of PAF on neuroblastoma and melanoma cells may be due to variations in PAF sensitivity.…”

Section: Discussionmentioning

confidence: 88%

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Platelet-activating Factor Mediates MMP-2 Expression and Activation via Phosphorylation of cAMP-response Element-binding Protein and Contributes to Melanoma Metastasis

Melnikova

Mourad-Zeidan

Lev

et al. 2006

Journal of Biological Chemistry

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Overexpression of cAMP-response element (CRE)-binding protein (CREB) and activating transcription factor (ATF) 1 contributes to melanoma progression and metastasis at least in part by promoting tumor cell survival and stimulating matrix metalloproteinase (MMP) 2 expression. However, little is known about the regulation of CREB and ATF-1 activities and their phosphorylation within the tumor microenvironment. We analyzed the effect of platelet-activating factor (PAF), a potent phospholipid mediator of inflammation, for its ability to activate CREB and ATF-1 in eight cultured human melanoma cell lines, and we found that PAF receptor (PAFR) was expressed in all eight lines. In metastatic melanoma cell lines, PAF induced CREB and ATF-1 phosphorylation via a PAFRmediated signal transduction mechanism that required pertussis toxin-insensitive G␣ q protein and adenylate cyclase activity and was antagonized by a cAMP-dependent protein kinase A and p38 MAPK inhibitors. Addition of PAF to metastatic A375SM cells stimulated CRE-dependent transcription, as observed in a luciferase reporter assay, without increasing the CRE DNA binding capacity of CREB. Furthermore, PAF stimulated the gelatinase activity of MMP-2 by activating transcription and MMP-2 expression. MMP-2 activation correlated with the PAF-induced increase in the expression of an MMP-2 activator, membrane type 1 MMP. PAF-induced expression of pro-MMP-2 was causally related to PAF-induced CREB and ATF-1 phosphorylation; it was prevented by PAFR antagonist and inhibitors of p38 MAPK and protein kinase A and was abrogated upon quenching of CREB and ATF-1 activities by forced overexpression of a dominant-negative form of CREB. PAFinduced MMP-2 activation was also down-regulated by p38 MAPK and protein kinase A inhibitors. Finally, PAFR antagonist PCA4248 inhibited the development of A375SM lung metastasis in nude mice. This result indicated that PAF acts as a promoter of melanoma metastasis in vivo. We proposed that metastatic melanoma cells overexpressing CREB/ATF-1 are better equipped than nonmetastatic cells to respond to PAF within the tumor microenvironment. cAMP-response element (CRE)2 -binding protein (CREB), activating transcription factor (ATF) 1, and CRE modulators are members of the large basic region leucine zipper superfamily of transcription factors that regulate gene expression in response to cAMP, intracellular Ca 2ϩ mobilization, and cell stimulation with growth factors (1). The ubiquitously expressed CREB and ATF-1 and the preferentially expressed (in neuroendocrine tissues) CRE modulator bind to complete and partial palindromic CRE DNA consensus sites 5Ј-TGACGTCA-3Ј and 5Ј-CGTCA-3Ј. These transcription factors induce genes involved in cellular metabolism and respiration, gene transcription, cell cycle regulation and cell survival, as well as growth factor and cytokine genes (reviewed in Ref. 1). The transcriptional activity of the DNA-bound CREB protein dimers is regulated by phosphorylation of the serine 133 site in the kinase-inducible domain, wh...

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Section: Discussioncontrasting

confidence: 77%

Section: Discussionmentioning

confidence: 88%

Platelet-activating Factor Mediates MMP-2 Expression and Activation via Phosphorylation of cAMP-response Element-binding Protein and Contributes to Melanoma Metastasis

Melnikova

Mourad-Zeidan

Lev

et al. 2006

Journal of Biological Chemistry

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“…Alternatively to the reports showing positive regulation of MMPs by PAF, Barletta et al showed that 300 nM PAF donwregulated the mRNA levels of MT1-MMP and MMP-2 and reduced levels of MMP-2 activation in isolated neuroblastoma cell clones [81]. These authors further reported that downregulation of MMPs inversely correlated with PAF-induced differentiation in these cells [81].…”

Section: Paf and Pafr-mediated Signal Transduction Pathwaysmentioning

confidence: 97%

Inflammation and melanoma growth and metastasis: The role of platelet-activating factor (PAF) and its receptor

Melnikova

Bar‐Eli

2007

Cancer Metastasis Rev

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An inflammatory tumor microenvironment fosters tumor growth, angiogenesis and metastatic progression. Platelet-activating factor (PAF) is an inflammatory biolipid produced from membrane glycerophospholipids. Through the activity of its G-protein coupled receptor, PAF triggers a variety of pathological reactions including tumor neo-angiogenesis. Several groups have demonstrated that inhibiting PAF-PAF receptor pathway at the level of a ligand or receptor results in an effective inhibition of experimental tumor growth and metastasis. In particular, our group has recently demonstrated that PAF receptor antagonists can effectively inhibit the metastatic potential of human melanoma cells in nude mice. Furthermore, we showed that PAF stimulated the phosphorylation of CREB and ATF-1 in metastatic melanoma cells, which resulted in overexpression of MMP-2 and MT1-MMP. Our data indicate that PAF acts as a promoter of melanoma metastasis in vivo. Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that these cells are better equipped to respond to PAF within the tumor microenvironment when compared to their non-metastatic counterparts.

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“…Cell lysates (200 g) were used to assess the activity of PKA, based on its ability to phosphorylate its specific substrate, Kemptide, using the PKA assay kit (Upstate Biotechnology). PKA activity was expressed as nanomoles of 32 P incorporated in Kemptide/min/g of protein and represented as percentage of control against time (control being set at 100%, for 10-min time point, p ϭ 0.038 for SQ-treated cells and p ϭ 0.009 for H-89-treated cells using two-sided Student's t test). (Fig.…”

Section: Paf Induces Activation Of Pertussis Toxin-insensitive G␣ Qmentioning

confidence: 99%

“…PAF has been shown to stimulate the expression and activity of MMPs in corneal epithelial cells (31). In neuroblastoma clones isolated from the human LaN1 neuroblastoma cell line, PAF exposure reduced the expression MMPs and activation of MMP2, resulting in inhibition of invasiveness through Matrigel by these cells (32). We have recently demonstrated that the stimulation of quiescent HUVECs with PAF induces increases in mRNA levels for TIMP2 and MMP14, resulting in coordinated increases in protein levels of both TIMP2 and MT1-MMP (55).…”

mentioning

confidence: 99%

Activation of Platelet-activating Factor Receptor-coupled Gαq Leads to Stimulation of Src and Focal Adhesion Kinase via Two Separate Pathways in Human Umbilical Vein Endothelial Cells

Deo

Bazán

Hunt

2004

Journal of Biological Chemistry

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Platelet-activating factor (PAF), a phospholipid second messenger, has diverse physiological functions, including responses in differentiated endothelial cells to external stimuli. We used human umbilical vein endothelial cells (HUVECs) as a model system. We show that PAF activated pertussis toxin-insensitive G␣ q protein upon binding to its seven transmembrane receptor. Elevated cAMP levels were observed via activation of adenylate cyclase, which activated protein kinase A (PKA) and was attenuated by a PAF receptor antagonist, blocking downstream activity. Phosphorylation of Src by PAF required G␣ q protein and adenylate cyclase activation; there was an absolute requirement of PKA for PAFinduced Src phosphorylation. Immediate (1 min) PAFinduced STAT-3 phosphorylation required the activation of G␣ q protein, adenylate cyclase, and PKA, and was independent of these intermediates at delayed (30 min) and prolonged (60 min) PAF exposure. PAF activated PLC␤3 through its G␣ q protein-coupled receptor, whereas activation of phospholipase C␥1 (PLC␥1) by PAF was independent of G proteins but required the involvement of Src at prolonged PAF exposure (60 min). We demonstrate for the first time in vascular endothelial cells: (i) the involvement of signaling intermediates in the PAF-PAF receptor system in the induction of TIMP2 and MT1-MMP expression, resulting in the coordinated proteolytic activation of MMP2, and (ii) a receptor-mediated signal transduction cascade for the tyrosine phosphorylation of FAK by PAF. PAF exposure induced binding of p130 Cas , Src, SHC, and paxillin to FAK. Clearly, PAF-mediated signaling in differentiated endothelial cells is critical to endothelial cell functions, including cell migration and proteolytic activation of MMP2.

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Platelet Activating Factor Inhibits the Expression of Matrix Metalloproteinases and Affects Invasiveness and Differentiation in a System of Human Neuroblastoma Clones

Cited by 7 publications

References 33 publications

Platelet-activating Factor Mediates MMP-2 Expression and Activation via Phosphorylation of cAMP-response Element-binding Protein and Contributes to Melanoma Metastasis

Platelet-activating Factor Mediates MMP-2 Expression and Activation via Phosphorylation of cAMP-response Element-binding Protein and Contributes to Melanoma Metastasis

Inflammation and melanoma growth and metastasis: The role of platelet-activating factor (PAF) and its receptor

Activation of Platelet-activating Factor Receptor-coupled Gαq Leads to Stimulation of Src and Focal Adhesion Kinase via Two Separate Pathways in Human Umbilical Vein Endothelial Cells

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