PGE<sub>2</sub>inhibits apoptosis in human adenocarcinoma Caco-2 cell line through Ras-PI3K association and cAMP-dependent kinase A activation

Leone, Vincenza; Palma, Antonella Di; Ricchi, Paolo; Acquaviva, Fabio; Giannouli, Maria; Prisco, Anna Maria Di; Iuliano, Francesca; Acquaviva, Angela Maria

doi:10.1152/ajpgi.00584.2006

Cited by 81 publications

(65 citation statements)

References 36 publications

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“…Here, we demonstrate the presence of EP 1 -EP 4 receptors in differentiated Caco-2 cells, suggesting a higher basolateral localization. Moreover, EP receptors were described to be involved in the regulation of various cellular processes in Caco-2 cells (cell proliferation and adhesion, interleukin synthesis, and PP) (15,26,27,31,43,45).…”

Section: Resultsmentioning

confidence: 99%

PGE₂promotes Ca²⁺-mediated epithelial barrier disruption through EP₁and EP₄receptors in Caco-2 cell monolayers

Rodríguez-Lagunas

Martín‐Venegas

Moreno

et al. 2010

American Journal of Physiology-Cell Physiology

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We recently demonstrated that PGE2 induces the disruption of the intestinal epithelial barrier function. In the present study, our objectives were to study the role of PGE2 receptors (EP1-EP4) and the signaling pathways involved in this event. Paracellular permeability (PP) was assessed in differentiated Caco-2 cell cultures from D-mannitol fluxes and transepithelial electrical resistance (TER) in the presence of different PGE 2 receptor agonists (carbacyclin, sulprostone, butaprost, ONO-AE1-259, ONO-AE-248, GR63799, and ONO-AE1-329) and antagonists (ONO-8711, SC-19220, AH-6809, ONO-AE3-240, ONO-AE3-208, and AH-23848). The results indicate that EP1 and EP4 but not EP2 and EP3 might be involved in PP regulation. These effects were mediated through PLC-inositol trisphosphate (IP 3)-Ca 2ϩ and cAMP-PKA signaling pathways, respectively. We also observed an increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) strengthened by cAMP formation indicating a cross talk interaction of these two pathways. Moreover, the participation of a conventional PKC isoform was shown. The results also indicate that the increase in PP may be correlated with the redistribution of occludin, zona occludens 1 (ZO-1), and the perijunctional actin ring together with an increase in myosin light chain kinase activity. Although the disruption of epithelial barrier function observed in inflammatory bowel disease (IBD) patients has been traditionally attributed to cytokines, the present study focused on the role of PGE2 in PP regulation, as mucosal levels of this eicosanoid are also increased in these inflammatory processes. paracellular permeability; intestine; tight junctions; eicosanoids; arachidonic acid cascade THE STRUCTURAL INTEGRITY OF the epithelium is maintained by three distinct adhesion systems: tight junctions (TJ), adherent junctions, and desmosomes. Of these, TJ are the most apical component and are the rate-limiting step for paracellular permeability (PP). In addition, TJ constitute the interface (fence) between apical and basolateral membrane domains (32). TJ are multiprotein complexes composed of transmembrane proteins associated with the cytoskeletal perijunctional ring of actin and myosin and with cytosolic proteins involved in cell signaling and vesicle trafficking. Five transmembrane proteins of the junctional complex have been identified in recent years: occludin, the claudin family, tricellulin, crumbs, and junctional adhesion molecules. These proteins are associated with a wide spectrum of cytosolic proteins, of which zona occludens (ZO) 1, ZO-2, ZO-3, AF6, and cingulin are described as forming the nexus with cytoskeletal proteins (42). PGE 2 is an inflammatory mediator that has pleiotropic effects on signal transduction and exerts its biological action through binding to four specific membrane receptor subtypes, EP 1 , EP 2 , EP 3 , and EP 4 , which are widely distributed and have different tissue expression. PGE 2 stimulation leads to activation of different G proteins, depending on the type of EP subtype engaged, i...

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Section: Resultsmentioning

confidence: 99%

PGE₂promotes Ca²⁺-mediated epithelial barrier disruption through EP₁and EP₄receptors in Caco-2 cell monolayers

Rodríguez-Lagunas

Martín‐Venegas

Moreno

et al. 2010

American Journal of Physiology-Cell Physiology

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“…Although the involvement of this pathway in mediating apoptosis was demonstrated in several reports, the data are still controversial. Apoptosis induced by serum deprivation (35) or by treatment with Fas ligand or staurosporine (7) could be suppressed by elevation of cAMP through activation of tmAC. Alternatively, several studies demonstrated that cellular elevation of cAMP itself may lead to apoptosis and suppress proliferation (5,6).…”

Section: Discussionmentioning

confidence: 99%

Soluble Adenylyl Cyclase Controls Mitochondria-dependent Apoptosis in Coronary Endothelial Cells

Kumar

Kostin

Flacke

et al. 2009

Journal of Biological Chemistry

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The cAMP signaling pathway plays an essential role in modulating the apoptotic response to various stress stimuli. Until now, it was attributed exclusively to the activity of the G-protein-responsive transmembrane adenylyl cyclase. In addition to transmembrane AC, mammalian cells possess a second source of cAMP, the ubiquitously expressed soluble adenylyl cyclase (sAC). However, the role of this cyclase in apoptosis was unknown. A mitochondrial localization of this cyclase has recently been demonstrated, which led us to the hypothesis that sAC may play a role in apoptosis through modulation of mitochondria-dependent apoptosis. To prove this hypothesis, apoptosis was induced by simulated in vitro ischemia or by acidosis, which is an important component of ischemia. Suppression of sAC activity with the selective inhibitor KH7 or sAC knockdown by small interfering RNA transfection abolished endothelial apoptosis. Furthermore, pharmacological inhibition or knockdown of protein kinase A, an important cAMP target, demonstrated a significant anti-apoptotic effect. Analysis of the underlying mechanisms revealed (i) the translocation of sAC to mitochondria under acidic stress and (ii) activation of the mitochondrial pathway of apoptosis, i.e. cytochrome c release and caspase-9 cleavage. sAC inhibition or knockdown abolished the activation of the mitochondrial pathway of apoptosis. Analysis of mitochondrial co-localization of Bcl-2 family proteins demonstrated sAC-and protein kinase A-dependent translocation of Bax to mitochondria. Taken together, these results suggest the important role of sAC in modulating the mitochondria-dependent pathway of apoptosis in endothelial cells. Increasing evidence suggests that apoptosis of endothelial cells (EC)3 may be responsible for acute and chronic vascular diseases, e.g. through atherogenesis (1), endothelial dysfunction (2), or thrombosis (3). Within several signaling mechanisms, a cAMP-dependent signaling pathway plays a substantial role in mediating apoptotic cell death induced by various stress factors. Elevation of the cellular cAMP either by forskolin-induced stimulation of the G-protein-responsive transmembrane adenylyl cyclase (tmAC) or by treatment with cAMP analogs has been shown to lead to both induction and suppression of apoptosis in different cell types (4 -7). This discrepancy may be due to differences in cell types and experimental models. Alternatively, a lack of specificity of tmAC-induced signals, especially directed to distant intracellular targets like mitochondria, may be a cause of the discrepancy. Indeed, the classical model of cAMP signaling requires the diffusion of cAMP from plasma membrane-localized tmAC to targets localized throughout the cell. Diffusion of cAMP throughout the cytosol makes it difficult to selectively activate distally localized targets without also activating more proximal targets. Therefore, such diffusion of cAMP would likely diminish specificity, selectivity, and signal strength. This model is further complicated by the presence of p...

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“…This finding is in agreement with previous studies, which show that EP2 is the functional receptor of PGE 2 and activates PKA by regulating cAMP signaling pathway. 19 To explore the functional effect of DA on EP2 receptor signaling, we investigated the translocation of the PKA catalytic subunit to the nucleus in DA-and PGE 2 -treated HL-60 cells. DA was found to inhibit PGE 2 -induced increase in translocation of the catalytic subunit (Fig.…”

Section: Da Treatment Reduces the Pge 2 -Induced Survival Effect In Hmentioning

confidence: 99%

Decursinol angelate inhibits PGE₂-induced survival of the human leukemia HL-60 cell line via regulation of the EP2 receptor and NFκB pathway

Shehzad

Islam

Ahn

et al. 2016

Cancer Biology & Therapy

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Decursinol angelate (DA), an active pyranocoumarin compound from the roots of Angelica gigas, has been reported to possess anti-inflammatory and anti-cancer activities. In a previous study, we demonstrated that prostaglandin E 2 (PGE 2 ) plays a survival role in HL-60 cells by protecting them from the induction of apoptosis via oxidative stress. Flow cytometry and Hoechst staining revealed that PGE 2 suppresses menadione-induced apoptosis, cell shrinkage, and chromatin condensation, by blocking the generation of reactive oxygen species. Treatment of DA was found to reverse the survival effect of PGE 2 as well as restoring the menadione-mediated cleavage of caspase-3, lamin B, and PARP. DA blocked PGE 2 -induced activation of the EP2 receptor signaling pathway, including the activation of PKA and the phosphorylation of CREB. DA also inhibited PGE 2 -induced expression of cyclooxygenase-2 and the activation of the Ras/Raf/ Erk pathway, which activates downstream targets for cell survival. Finally, DA greatly reduced the PGE 2 -induced activation of NF-kB p50 and p65 subunits. These results elucidate a novel mechanism for the regulation of cell survival and apoptosis, and open a gateway for further development and combinatory treatments that can inhibit PGE 2 in cancer cells.

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PGE₂inhibits apoptosis in human adenocarcinoma Caco-2 cell line through Ras-PI3K association and cAMP-dependent kinase A activation

Cited by 81 publications

References 36 publications

PGE₂promotes Ca²⁺-mediated epithelial barrier disruption through EP₁and EP₄receptors in Caco-2 cell monolayers

PGE₂promotes Ca²⁺-mediated epithelial barrier disruption through EP₁and EP₄receptors in Caco-2 cell monolayers

Soluble Adenylyl Cyclase Controls Mitochondria-dependent Apoptosis in Coronary Endothelial Cells

Decursinol angelate inhibits PGE₂-induced survival of the human leukemia HL-60 cell line via regulation of the EP2 receptor and NFκB pathway

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PGE2inhibits apoptosis in human adenocarcinoma Caco-2 cell line through Ras-PI3K association and cAMP-dependent kinase A activation

Cited by 81 publications

References 36 publications

PGE2promotes Ca2+-mediated epithelial barrier disruption through EP1and EP4receptors in Caco-2 cell monolayers

PGE2promotes Ca2+-mediated epithelial barrier disruption through EP1and EP4receptors in Caco-2 cell monolayers

Soluble Adenylyl Cyclase Controls Mitochondria-dependent Apoptosis in Coronary Endothelial Cells

Decursinol angelate inhibits PGE2-induced survival of the human leukemia HL-60 cell line via regulation of the EP2 receptor and NFκB pathway

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PGE₂inhibits apoptosis in human adenocarcinoma Caco-2 cell line through Ras-PI3K association and cAMP-dependent kinase A activation

PGE₂promotes Ca²⁺-mediated epithelial barrier disruption through EP₁and EP₄receptors in Caco-2 cell monolayers

PGE₂promotes Ca²⁺-mediated epithelial barrier disruption through EP₁and EP₄receptors in Caco-2 cell monolayers

Decursinol angelate inhibits PGE₂-induced survival of the human leukemia HL-60 cell line via regulation of the EP2 receptor and NFκB pathway