Abstract
Neuropeptides are autocrine and paracrine signalling factors and mainly bind to G protein-coupled receptors (GPCRs) to trigger intracellular secondary messenger release including adenosine 3′, 5′-cyclic monophosphate (cAMP), thus modulating cancer progress in different kind of tumours. As one of the downstream effectors of cAMP, exchange proteins directly activated by cAMP (EPACs) play dual roles in cancer proliferation and metastasis. More evidence about the relationship between neuropeptides and EPAC pathways have been proposed for their potential role in cancer development; hence, this review focuses on the role of neuropeptide/GPCR system modulation of cAMP/EPACs pathways in cancers. The correlated downstream pathways between neuropeptides and EPACs in cancer cell proliferation, migration, and metastasis is discussed to glimmer the direction of future research.
Highlights
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Studies on the role of the neuropeptide/G protein-coupled receptors (GPCRs) system in cancer development underscore the complexity of the neuroendocrine/GPCR/cAMP pathway
Multiple neuropeptide GPCRs are essential intracellular cAMP level modulators; it is necessary to investigate the relationship between those neuropeptide/GPCRsystems as well as the down-stream pathways mediated by the cAMP effectors exchange proteins directly activated by cAMP (EPAC) and protein kinase A (PKA)
Summary
Neuropeptides are small chain polypeptides that are synthesized and released by neurons through a regulated secretory route. Neuropeptide-GPCRs interactions can lead to the synthesis of classic second messengers such as intra-cytoplasmic calcium (Ca2+), diacylglycerol (DAG), and cAMP These can stimulate enormous cellular changes such as actin organization or rapid tyrosine phosphorylation of multiple substrates including the non-receptor tyrosine kinases PAK and Pyk and the adaptor proteins p130 CAS and paxillin [4]. EPACs have similar protein structure as other cAMP-activated guanine nucleotide exchange factors (cAMP-GEFs) including N-terminal cAMP-binding domains and a Cterminal GEF domain. According to the sequences and domain structure, three different isoforms of EPAC protein family were identified and defined as EPAC1, EPAC2 and REPAC (for related to EPAC) They consist of N-terminal autoinhibitory region (a dishevelled Egl-10, pleckstrin homology domain, and cyclic nucleotide binding domains) and C-terminal catalytic region (a RAS exchange motif, a RAS-association domain, and a CDC25 homology domain) (Figure 1) [22,23,24]. EPAC proteins targeted drugs could be the candidates for therapy towards cAMP pathway-mediated diseases in the future
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