PDE4 and Epac1 Synergistically Promote Rectal Carcinoma via the cAMP Pathway

Abstract

Objective. To assess the expression levels of exchange protein 1 directly activated by cAMP (Epac1) and phosphodiesterase 4 (PDE4) in rectal carcinoma, and their associations with clinicopathological indexes. In addition, the associations of PDE4 and Epac1 with A-kinase anchor protein 95, connexin 43, cyclin D1, and cyclin E1 were evaluated. Methods. The PV-9000 two-step immunohistochemistry method was used to determine protein expression in 44 rectal carcinoma tissue samples and 16 paracarcinoma tissue specimens. Results. The positive rate of PDE4 protein expression in rectal carcinoma tissues was higher than that of paracarcinoma tissues (59.09% vs. 12.5%, P<0.05). Similar findings were obtained for Epac1 (55% vs. 6.25%, P<0.05). No significant associations of PDE4 and Epac1 with degree of differentiation, histological type, and lymph node metastasis were found in rectal carcinoma (P>0.05). Correlations between PDE4 and Epac1, PDE4 and Cx43, PDE4 and cyclin E1, and Epac1 and Cx43 were observed (all P<0.05). There was no correlation between the other protein pairs examined (P>0.05). Conclusion. PDE4 and Epac1 expression levels are increased in rectal carcinoma tissues, suggesting that the two proteins may be involved in the development of this malignancy. Meanwhile, correlations between PDE4 and Epac1, PDE4 and Cx43, PDE4 and cyclin E1, and Epac1 and Cx43 suggested synergistic effects of these proteins in promoting rectal carcinoma.

In silicoapproach: biological prediction of nordentatin derivatives as anticancer agent inhibitors in the cAMP pathway

“…where the KS theory that states the ground state energy in a system is a functional application, as shown in eqn (2).…”

“…1 Signal transduction plays an important role in physiological processes that are related to resistance and cell growth in normal cells. 2 The signal received from ligand-bound GPCRs is forwarded by the G protein, which consists of 3 subunits, namely protein a, which is bound to guanosine diphosphate (GDP), protein b, and protein g. The transmitted signal changes the GDP bound to the a-protein to guanosine triphosphate (GTP), activating the a-protein. The activated a protein binds to the enzyme adenylyl cyclase, which plays a role in the phosphorylation process of changing adenosine triphosphate (ATP) into cAMP, a second messenger that activates a protein kinase.…”

The Role of Epac in Cancer Progression

“…Epac regulates cancer cells proliferation and survival in a wide variety of cancers by targeting key signaling pathways involved in cell mitogenesis, inflammation, and metabolic reprogramming. Cyclin B1 and CDK1 [64] Rectal cancer Promotes Cyclin E1-Cnx43 [65] Renal cancer Attenuates PI3K [66] Numerous studies evidently show that Epac enhances prostate cancer cells proliferation ( Figure 2). Epac activates the extracellular response kinase 1/2 (ERK1/2) and the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathways, both of which converge at the mammalian target of rapamycin (mTOR) signaling [62,63].…”

“…Additionally, another study demonstrated that Epac promotes glioblastoma regression by mediating the inhibition of MAPK activity [52]. Similarly, Epac exhibits an anti-proliferative role in clear renal cell carcinoma in mediating vasoactive intestinal peptide (VIP)-induced inhibition of cell proliferation through the PI3K pathway [66].…”

Selective small-molecule EPAC activators

“…Many studies have suggested that EPAC signalling dysfunction plays a role in such diverse conditions as hypertension [47,48], diabetes [49], cancer [50,51], cardiac arrhythmia [52], and inflammatory pain [53]. EPAC1 has been shown to play a role in mitigating pro-inflammatory cytokine signalling in vascular endothelial cells (VECs), through induction of SOCS3 and subsequent inhibition of IL-6 signalling via the JAK/STAT3 pathway [54,55].…”