The cAMP effectors PKA and Epac activate endothelial NO synthase through PI3K/Akt pathway in human endothelial cells

García-Morales, Verónica; Luaces-Regueira, Maria; Campos‐Toimil, Manuel

doi:10.1016/j.bcp.2017.09.004

Cited by 45 publications

(40 citation statements)

References 37 publications

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“…There is evidence to suggest that the PI 3 ‐Kinase/Akt pathway can be activated in response to elevated cAMP . To determine whether activation of the PI 3 ‐Kinase/Akt pathway is involved in regulating the secretion of STC‐1 by trophoblasts we used the pharmacological modulator Ly294002.…”

Section: Resultsmentioning

confidence: 99%

Regulation of stanniocalcin‐1 secretion by BeWo cells and first trimester human placental tissue from normal pregnancies and those at increased risk of developing preeclampsia

et al. 2020

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Naila Abid, Joan Embola and Zoe Tryfonos contributed equally to this study.Abbreviations: 8 Br-cAMP, 8-Bromo adenosine-3', 5'-cyclic monophosphate; BSA, bovine serum albumin; cAMP, adenosine-3', 5'-cyclic monophosphate; DAB, 3,3′-diaminobenzidine; DP44mT, di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone; Epac, exchange proteins directly activated by cAMP; FCS, fetal calf serum; GSK-3β, glycogen synthase kinase-3β; hCG, human chorionic gonadotrophin; HIF, hypoxia-Inducible factor; HRE, hypoxia response element; IGF, insulin-like growth factor; IGFBP4, insulin-like growth factor binding protein; mTOR, mammalian target of rapamycin; mTORC, mammalian target of rapamycin complex; NDRG-1, N-myc downstream-regulated gene 1; NHS, National Health Service; PAPP-A, pregnancy-associated plasma protein-A; PBS, phosphate-buffered saline; PBST, phosphate-buffered saline with tween; PI 3 -Kinase, phosphatidylinositol-3 kinase; PKA, protein kinase A; SGK-1, serum and glucocorticoid-induced kinase-1; STC-1, stanniocalcin-1; TBS, tris-buffered saline; TBST, tris-buffered saline with tween. AbstractStanniocalcin-1 (STC-1) is a multi-functional glycosylated peptide present in the plasma of healthy women postpartum and increased further in pregnancies complicated by preeclampsia. Although the STC-1 gene is expressed by the placenta what regulates its secretion and from which cells at the feto-maternal interface is unknown.Here, we demonstrate for the first time that the syncytiotrophoblast and cytotrophoblast are a major site of STC-1 protein expression in first trimester placental tissue. Further, in response to low oxygen, first trimester chorionic villous tissue from pregnancies at increased risk of developing preeclampsia secreted significantly more STC-1 than normal tissue under the same conditions. Using the human trophoblast cell line BeWo we have shown that low oxygen increased the secretion of STC-1 but it required co-stimulation with the Adenosine-3', 5'-cyclic monophosphate (cAMP) analogue, 8-Bromo adenosine-3', 5'-cyclic monophosphate cAMP to reach significance. Inhibition of Hypoxia inducible factor 2α (HIF-2α) and the Phosphatidylinositol-3 kinase (PI 3 -Kinase)/AKT/Serum and glucocorticoid-induced kinase-1(SGK-1) pathway resulted in significant inhibition of STC-1 secretion. As both low oxygen and cAMP are known to play a central role in placental function, their regulation of STC-1 points to a potentially important role in the maintenance of a normal healthy pregnancy and we would hypothesize that it may act to protect against prolonged placental hypoxia seen in preeclampsia. K E Y W O R D Sfirst trimester, hypoxia, placenta, stanniocalcin-1, trophoblasts

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Section: Resultsmentioning

confidence: 99%

Regulation of stanniocalcin‐1 secretion by BeWo cells and first trimester human placental tissue from normal pregnancies and those at increased risk of developing preeclampsia

et al. 2020

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“…Protein kinase A (PKA) and exchange protein activated by cAMP (EPAC) are the main effectors of cAMP (50); however, it is unclear whether the anti-proliferative effect of cAMP in DLD-1 cells is dependent on PKA and/or EPAC. Notably, the cytotoxic effects of cAMP in normal and malignant B cells are independent of PKA and EPAC (21).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of phosphodiesterase 4D decreases the malignant properties of DLD‑1 colorectal cancer cells by repressing the AKT/mTOR/Myc signaling pathway

et al. 2019

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Colorectal cancer (CRC) is a complex disease involving numerous genetic abnormalities. One of the major characteristics of CRC is enhanced Wnt signaling caused by loss-of-function mutations in the adenomatous polyposis coli (APC) gene. Previously, it has been demonstrated that the majority of malignant phenotypes following APC deletion in adult murine small intestines could be rescued when Myc, a downstream target of the Wnt pathway, was deleted. This indicated that Myc is a critical regulator of CRC development following APC loss. Previous studies reported that cyclic adenosine 3',5'-monophosphate (cAMP) can influence the AKT/mammalian target of rapamycin (mTOR) survival pathway in cancer and Myc is a critical downstream molecule of AKT/mTOR signaling. Phosphodiesterase 4D (PDE4D), a member of the cAMP-specific PDE4 family, has been associated with drug resistance in CRC. However, the association between PDE4D and Myc remains unclear. To investigate the potential role of PDE4D in Myc regulation in CRC, the present study evaluated the expression levels of PDE4 subtypes in DLD-1 CRC cells. Additionally, the effects of PDE4 inhibitors on Myc expression and oncogenic properties were analyzed by western blot analysis, reverse transcription-quantitative polymerase chain reaction, colony formation and soft agar assays. It was demonstrated that cAMP/PDE4D signals serve a critical role in regulating Myc expression in DLD-1 CRC cells. Furthermore, PDE4D was identified to be a main hydrolyzer of cAMP and suppression of PDE4D using selective inhibitors of PDE4 increased intracellular cAMP levels, which resulted in a marked decrease in the oncogenic properties of DLD-1 cells, including colony formation, cell proliferation and anchorage-independent growth. Notably, the current data imply that cAMP represses Myc expression via the downregulation of AKT/mTOR signaling, which was abolished by high PDE4D activities in DLD-1 cells. Additionally, a natural polyphenol resveratrol in combination with forskolin elevated the concentration of cAMP and enhanced the expression of Myc and the malignant phenotype of DLD-1 cells, reproducing the effect of known chemical inhibitors of PDE4. In conclusion, the present study identified that cAMP/PDE4D signaling is a critical regulator of Myc expression in DLD-1 and possibly other CRC cells.

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“…A number of studies indicated that the cAMP pathway is an upstream signaling event. Garcia-Morales et al (33) found that the cAMP effector PKA was responsible for activation of the PI3K/AKT pathway and NO synthase. Suzuki et al (34) reported that cAMP/PKA signaling could…”

Section: Discussionmentioning

confidence: 99%

The flavonol glycoside icariin promotes bone formation in growing rats by activating the cAMP signaling pathway in primary cilia of osteoblasts

Shi

Gao

Wang

et al. 2017

Journal of Biological Chemistry

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Icariin, a prenylated flavonol glycoside isolated from the herb , has been considered as a potential alternative therapy for osteoporosis. Previous research has shown that, unlike other flavonoids, icariin is unlikely to act via the estrogen receptor, but its exact mechanism of action is unknown. In this study, using rat calvarial osteoblast culture and rat bone growth models, we demonstrated that icariin promotes bone formation by activating the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway requiring functional primary cilia of osteoblasts. We found that icariin increases the peak bone mass attained by young rats and promotes the maturation and mineralization of rat calvarial osteoblasts. Icariin activated cAMP/PKA/CREB signaling of the osteoblasts by increasing intracellular cAMP levels and facilitating phosphorylation of both PKA and CREB. Blocking cAMP/PKA/CREB signaling with inhibitors of the cAMP-synthesizing adenylyl cyclase (AC) and PKA inhibitors significantly inhibited the osteogenic effect of icariin in the osteoblasts. Icariin-activated cAMP/PKA/CREB signaling was localized to primary cilia, as indicated by localization of soluble AC and phosphorylated PKA. Furthermore, blocking ciliogenesis via siRNA knockdown of a cilium assembly protein, IFT88, inhibited icariin-induced PKA and CREB phosphorylation and also abolished icariin's osteogenic effect. Finally, several of these outcomes were validated in icariin-treated rats. Together, these results provide new insights into icariin function and its mechanisms of action and strengthen existing ties between cAMP-mediated signaling and osteogenesis.

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The cAMP effectors PKA and Epac activate endothelial NO synthase through PI3K/Akt pathway in human endothelial cells

Cited by 45 publications

References 37 publications

Regulation of stanniocalcin‐1 secretion by BeWo cells and first trimester human placental tissue from normal pregnancies and those at increased risk of developing preeclampsia

Regulation of stanniocalcin‐1 secretion by BeWo cells and first trimester human placental tissue from normal pregnancies and those at increased risk of developing preeclampsia

Inhibition of phosphodiesterase 4D decreases the malignant properties of DLD‑1 colorectal cancer cells by repressing the AKT/mTOR/Myc signaling pathway

The flavonol glycoside icariin promotes bone formation in growing rats by activating the cAMP signaling pathway in primary cilia of osteoblasts

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