The future of EPAC-targeted therapies: agonism versus antagonism

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Highlights

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Although tractable to drug development, targeting of cAMP signalling has side effects.
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Selectively targeting EPAC1 and EPAC2 cAMP sensor enzymes may limit some of these off-target effects.
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EPAC agonists could be used to treat vascular inflammation (EPAC1) or type 2 diabetes (EPAC2).
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EPAC1 and EPAC2 antagonists could be used to treat heart disease.

Abstract

Pharmaceutical manipulation of cAMP levels exerts beneficial effects through the regulation of the exchange protein activated by cAMP (EPAC) and protein kinase A (PKA) signalling routes. Recent attention has turned to the specific regulation of EPAC isoforms (EPAC1 and EPAC2) as a more targeted approach to cAMP-based therapies. For example, EPAC2-selective agonists could promote insulin secretion from pancreatic β cells, whereas EPAC1-selective agonists may be useful in the treatment of vascular inflammation. By contrast, EPAC1 and EPAC2 antagonists could both be useful in the treatment of heart failure. Here we discuss whether the best way forward is to design EPAC-selective agonists or antagonists and the current strategies being used to develop isoform-selective, small-molecule regulators of EPAC1 and EPAC2 activity.

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Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis.

Suyun Huang, M. Liu, Raymond Sawaya … (2004)

The expression of matrix metalloproteinase-2 (MMP-2) has been linked with tumor invasion, angiogenesis, and metastasis. However, the molecular basis for MMP-2 overexpression in tumor cells remains unclear. In this study, by using K-1735 melanoma system, we demonstrated that highly metastatic C4, M2, and X21 tumor cells express elevated MMP-2 mRNA and enzymatic activity, whereas poorly metastatic C10, C19, and C23 tumor cells express much lower levels. Moreover, a concomitant elevated Stat3 activity has been detected in these metastatic tumor cells that overexpress MMP-2. Transfection of constitutively activated Stat3 into poorly metastatic C23 tumor cells directly activated the MMP-2 promoter, whereas the expression of a dominant-negative Stat3 in highly metastatic C4 tumor cells inhibited the MMP-2 promoter. A high-affinity Stat3-binding element was identified in the MMP-2 promoter and Stat3 protein bound directly to the MMP-2 promoter. Blockade of activated Stat3 through expression of a dominant-negative Stat3 significantly suppressed MMP-2 expression in the metastatic tumor cells. Therefore, overexpression of MMP-2 in the metastatic melanoma cells can be attributed to elevated Stat3 activity, and Stat3 upregulates the transcription of MMP-2 through direct interaction with the MMP-2 promoter. Furthermore, blockade of activated Stat3 in highly metastatic C4 cells significantly suppressed the invasiveness of the tumor cells, inhibited tumor growth, and prevented metastasis in nude mice. Collectively, these studies suggest that Stat3 signaling directly regulates MMP-2 expression, tumor invasion, and metastasis, and that Stat3 activation might be a crucial event in the development of metastasis.

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Cytokines and atherosclerosis: a comprehensive review of studies in mice

Robert Kleemann, Susanne Zadelaar, Teake Kooistra (2008)

In the past few years, inflammation has emerged as a major driving force of atherosclerotic lesion development. It is now well-established that from early lesion to vulnerable plaque formation, numerous cellular and molecular inflammatory components participate in the disease process. The most prominent cells that invade in evolving lesions are monocyte-derived macrophages and T-lymphocytes. Both cell types produce a wide array of soluble inflammatory mediators (cytokines, chemokines) which are critically important in the initiation and perpetuation of the disease. This review summarizes the currently available information from mouse studies on the contribution of a specified group of cytokines expressed in atherosclerotic lesions, viz. interleukins (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12, IL-18, IL-20) and macrophage-associated cytokines [tumour necrosis factor-α (TNF-α); macrophage migration inhibitory factor (MIF); interferon-γ (IFN-γ); colony stimulating factors G-CSF,-M-CSF,-GM-CSF) to atherogenesis. Emphasis is put on the consistency of the effects of these cytokines, i.e. inasmuch an effect depends on the experimental approach applied (overexpression/deletion, strain, gender, dietary conditions, and disease stage). An important outcome of this survey is (i) that only for a few cytokines there is sufficient consistent data allowing classifying them as typically proatherogenic (IL-1, IL-12, IL-18, MIF, IFN-γ, TNF-α, and M-CSF) or antiatherogenic (IL-10) and (ii) that some cytokines (IL-4, IL-6 and GM-CSF) can exert pro- or anti-atherogenic effects depending on the experimental conditions. This knowledge can be used for improved early detection, prevention and treatment of atherosclerosis.

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Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP.

Harumi Takahashi, Jun-ichi Miyazaki, Atsuko Tamamoto … (2007)

cAMP is well known to regulate exocytosis in various secretory cells, but the precise mechanism of its action remains unknown. Here, we examine the role of cAMP signaling in the exocytotic process of insulin granules in pancreatic beta cells. Although activation of cAMP signaling alone does not cause fusion of the granules to the plasma membrane, it clearly potentiates both the first phase (a prompt, marked, and transient increase) and the second phase (a moderate and sustained increase) of glucose-induced fusion events. Interestingly, all granules responsible for this potentiation are newly recruited and immediately fused to the plasma membrane without docking (restless newcomer). Importantly, cAMP-potentiated fusion events in the first phase of glucose-induced exocytosis are markedly reduced in mice lacking the cAMP-binding protein Epac2 (Epac2(ko/ko)). In addition, the small GTPase Rap1, which is activated by cAMP specifically through Epac2 in pancreatic beta cells, mediates cAMP-induced insulin secretion in a protein kinase A-independent manner. We also have developed a simulation model of insulin granule movement in which potentiation of the first phase is associated with an increase in the insulin granule density near the plasma membrane. Taken together, these data indicate that Epac2/Rap1 signaling is essential in regulation of insulin granule dynamics by cAMP, most likely by controlling granule density near the plasma membrane.

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Author and article information

Contributors

Stephen J. Yarwood

Journal

Journal ID (nlm-ta): Trends Pharmacol Sci

Journal ID (iso-abbrev): Trends Pharmacol. Sci

Title: Trends in Pharmacological Sciences

Publisher: Published By Elsevier In Association With The International Union Of Pharmacology

ISSN (Print): 0165-6147

ISSN (Electronic): 1873-3735

Publication date PMC-release: 1 April 2015

Publication date (Print): April 2015

Volume: 36

Issue: 4

Pages: 203-214

Affiliations

[1 ]Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK

[2 ]School of Pharmacy, University of Bradford, Bradford BD7 1DP, UK

Article

Publisher ID: S0165-6147(15)00022-X

DOI: 10.1016/j.tips.2015.02.003

PMC ID: 4392396

PubMed ID: 25744542

SO-VID: 636c4819-0b15-44c8-8ddf-c783b460ea7c

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This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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The future of EPAC-targeted therapies: agonism versus antagonism

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Karger: Endocrinology

Most cited references 96

Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis.

Cytokines and atherosclerosis: a comprehensive review of studies in mice

Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP.

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