Phosphodiesterase inhibitors control A172 human glioblastoma cell death through cAMP-mediated activation of protein kinase A and Epac1/Rap1 pathways

Moon, Eun‐Yi; Lee, Geunhee; Lee, Myung-Shik; Kim, Hwan‐Mook; Lee, Jae‐Wook

doi:10.1016/j.lfs.2011.12.010

Cited by 40 publications

(44 citation statements)

References 26 publications

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“…Similarly, induction of G 1 cell-cycle arrest by cAMP analogs correlates with PKA activation in A172 glioma cells [54]. Increase in PKA activity has also been reported to be essential for the anti-tumorigenic effects of ( R,R ′)-MNF in melanoma cell lines [22].…”

Section: Discussionmentioning

confidence: 99%

Concurrent activation of β 2 -adrenergic receptor and blockage of GPR55 disrupts pro-oncogenic signaling in glioma cells

Wnorowski

Such

Paul³

et al. 2017

Cellular Signalling

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Activation of β2-adrenergic receptor (β2AR) and deorphanized GPR55 has been shown to modulate cancer growth in diverse tumor types in vitro and in xenograft models in vivo. (R,R′)-4′-methoxy-1-naphthylfenoterol [(R,R′)-MNF] is a bivalent compound that agonizes β2AR but inhibits GPR55-mediated pro-oncogenic responses. Here, we investigated the molecular mechanisms underlying the anti-tumorigenic effects of concurrent β2AR activation and GPR55 blockade in C6 glioma cells using (R,R′)-MNF as a marker ligand. Our data show that (R,R′)-MNF elicited G1-phase cell cycle arrest and apoptosis, reduced serum-inducible cell motility, promoted the phosphorylation of PKA target proteins, and inhibited constitutive activation of ERK and AKT in the low nanomolar range, whereas high nanomolar levels of (R,R′)-MNF were required to block GPR55-mediated cell motility. siRNA knockdown and pharmacological inhibition of β2AR activity were accompanied by significant upregulation of AKT and ERK phosphorylation, and selective alteration in (R,R′)-MNF responsiveness. The effects of agonist stimulation of GPR55 on various readouts, including cell motility assays, were suppressed by (R,R′)-MNF. Lastly, a significant increase in phosphorylation-mediated inactivation of β-catenin occurred with (R,R′)-MNF, and we provided new evidence of (R,R′)-MNF-mediated inhibition of oncogenic β-catenin signaling in a C6 xenograft tumor model. Thus, simultaneous activation of β2AR and blockade of GPR55 may represent a novel therapeutic approach to combat the progression of glioblastoma cancer.

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Section: Discussionmentioning

confidence: 99%

Concurrent activation of β 2 -adrenergic receptor and blockage of GPR55 disrupts pro-oncogenic signaling in glioma cells

Wnorowski

Such

Paul³

et al. 2017

Cellular Signalling

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“…Moon et al found that PKA and Epac1 activators induced the increased basal level of cell death and G2/M phase arrest in A172 human glioblastoma cells [32], which suggested that PKA and Epac1-mediated signaling pathways could participate in the regulation of cell cycle. Furthermore, Sun et al [33] reported that high glucose ambience (HGA) increased the proportion of HK-2 cells in the G0/G1 phase, and the expression of p-AKT, the cyclin-dependent kinase inhibitors p21 and p27, was also increased, while the activity of CDK4 was decreased.…”

Section: Discussionmentioning

confidence: 99%

Epac1 knockdown inhibits the proliferation of ovarian cancer cells by inactivating AKT/Cyclin D1/CDK4 pathway in vitro and in vivo

Gao

Bast

et al. 2016

Med Oncol

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Ovarian cancer is the leading cause of death among gynecological malignancies, and high grade serous ovarian carcinoma is the most common and most aggressive subtype. Recently, it was demonstrated that cAMP mediates protein kinase A-independent effects through Epac (exchange protein directly activated by cAMP) proteins. Epac proteins, including Epac1 and Epac2, are implicated in several diverse cellular responses, such as insulin secretion, exocytosis, cellular calcium handling and formation of cell-cell junctions. Several reports document that Epac1 could play vital roles in promoting proliferation, invasion and migration of some cancer cells. However, the expression levels and roles of Epac1 in ovarian cancer have not been investigated. In the present study, we detected the expression levels of Epac1 mRNA and protein in three kinds of ovarian cancer cells SKOV3, OVCAR3 and CAOV3. Furthermore, the effect of Epac1 knockdown on the proliferation and apoptosis of SKOV3 and OVCAR3 cells was evaluated in vitro and in vivo. The results showed that there was higher expression of Epac1 mRNA and protein in SKOV3 and OVCAR3 cells. Epac1 knockdown inhibited the proliferation of SKOV3 and OVCAR3 cells in vitro and in vivo. Decreased proliferation may be due to downregulation of Epac1-induced G1 phase arrest by inactivating the AKT/Cyclin D1/CDK4 pathway, but not to alterations in the MAPK pathway or to apoptosis. Taken together, our data provide new insight into the essential role of Epac1 in regulating growth of ovarian cancer cells and suggest that Epac1 might represent an attractive therapeutic target for treatment of ovarian cancer.

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“…It is reported that in A172 and U87MG human glioblastoma cells, PKA and EPAC1 pathways synergistically promote cAMP-induced cell death and cell cycle arrest [34], while in clear renal cell carcinoma (cRCC) A498 cells, growth-inhibitory response to vasoactive intestinal peptide (VIP) is shown to be mediated by EPAC/PI3K pathway [35]. In contrast, EPAC1 promotes cell proliferation and survival by up-regulating Ras/MAPK and PI3K/AKT/mTOR signaling in prostate cancer cells [36,37].…”

Section: Epac1 In Cancer Cell Proliferation and Apoptosismentioning

confidence: 99%

The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: implications for therapeutic intervention

Almahariq

Mei

Cheng

2016

ABBS

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The pleiotropic second messenger adenosine 3′,5′-cyclic monophosphate (cAMP) regulates a myriad of biological processes under both physiological and pathophysiological conditions. Exchange protein directly activated by cAMP 1 (EPAC1) mediates the intracellular functions of cAMP by acting as a guanine nucleotide exchange factor for the Ras-like Rap small GTPases. Recent studies suggest that EPAC1 plays important roles in immunomodulation, cancer cell migration/metastasis, and metabolism. These results, coupled with the successful development of EPAC-specific small molecule inhibitors, identify EPAC1 as a promising therapeutic target for cancer treatments.

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Phosphodiesterase inhibitors control A172 human glioblastoma cell death through cAMP-mediated activation of protein kinase A and Epac1/Rap1 pathways

Cited by 40 publications

References 26 publications

Concurrent activation of β 2 -adrenergic receptor and blockage of GPR55 disrupts pro-oncogenic signaling in glioma cells

Concurrent activation of β 2 -adrenergic receptor and blockage of GPR55 disrupts pro-oncogenic signaling in glioma cells

Epac1 knockdown inhibits the proliferation of ovarian cancer cells by inactivating AKT/Cyclin D1/CDK4 pathway in vitro and in vivo

The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: implications for therapeutic intervention

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