Browsing by Subject "Adenosine receptors"

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Open Access
Adenosine regulation of danger signaling
(2017-07) Akdemir, İmran
Metabolic and immune related activities converge as main triggers of adenosine accumulation in extracellular space. Adenosine by engaging adenosine A2A and A2B receptors strongly suppresses innate and adaptive immune responses. Although adenosine receptors are being targeted in preclinical and clinical studies, how different danger signals are regulated by adenosine is poorly understood. Here we showed that adenosine receptor stimulation strongly inhibited inflammatory responses while sparing Type-I interferon responses downstream of different danger signals in dendritic cells and macrophages. Mechanistically, danger signals associated with MyD88-dependent inflammatory pathways such as LPS and CpG but not the danger signals associated with IRF3/Type-I interferon pathways such as pA:U and cGAMP increase the expression of adenosine A2A and A2B receptors. Expression of anti-inflammatory NR4A1 was increased after adenosine receptor stimulation in the presence of TLR ligands known to activate MyD88 pathway but not in the presence of cGAMP and pA:U. Overall these results indicate that there is a differential modulation of danger signaling by adenosine rather than overall suppression. Our results have important implications for developing combinatorial approaches to target adenosine and danger signaling pathways to cure immune-related diseases.
Open Access
Characterization of extracellular purinergic signaling components in colorectal carcinoma
(2021-01) Uygur, Beste
Colorectal carcinoma is a heterogeneous disease which is the third leading cause of cancer-associated mortalities in the world. It is also reported to be the third most diagnosed cancer among other cancer types. The intracellular functions of purines and pyrimidines in energy transaction and nucleic acid synthesis reactions have been well-known and clarified. Notwithstanding, the extracellular roles played by purinergic signaling components in cancer initiation and progression was not disclosed thoroughly as yet and become more prominent day by day. The extracellular purinergic system may have growth-inhibiting or growth-promoting effects in tumors in a tissue and context-dependent manner. Indeed, the knowledge regarding the impact of these elements in colorectal cancer is immensely limited. Therefore, in this study, we focused on deciphering the involvement of several extracellular purinergic signaling components in colorectal cancer, which are mainly one of the enzymes involved in degradation process of ATP, PSE002, and one of the adenosine receptors, PSC003. To assess their roles in colorectal cancer, we generated stable knockout cell lines targeting these two genes separately by CRISPR/Cas9 gene editing as well as transiently depleted cell lines by RNA interference (RNAi). The depletion of PSE002 and also PSC003 promoted cell proliferation and their anchorage-independent growth in vitro. In addition to this, their loss resulted in enhanced epithelial-to-mesenchymal transition (EMT) by upregulating the expression of mesenchymal markers. Moreover, cell line-derived xenograft models (CDX) of PSE002 could corroborate in vitro findings and strikingly augmented tumor growth in vivo. Interestingly, the effects observed in colorectal cancer cell lines upon PSE002 silencing could not be seen upon pharmacological inhibition by PSE002-selective antagonist. Contrary to this, PSC003-selective antagonist led to increased proliferative capacity in colorectal cancer cell lines under normal or hypoxic conditions. Ultimately, our findings provide a different perspective to extracellular adenosine signaling and claim that these targets act as tumor suppressor genes in colorectal carcinoma which should be taken into consideration for selecting therapeutic strategies against colorectal cancer.
Open Access
Molecular mechanism for adenosine regulation of dendritic cells
(2017-05) Kayhan, Merve
Cell death, inflammation or other cellular stress factors cause accumulation of adenosine in the extracellular space. Adenosine has immunosuppressive effects on antigen presenting cells. However, molecular mechanisms for adenosine regulation of dendritic cells are poorly understood. Here we showed that adenosine receptor signaling promotes an antiinflammatory dendritic cell phenotype. While adenosine receptor signaling increased intracellular cAMP levels, phosphoactivation of major inflammatory pathways such as MAPKs, NF-κB and IRF3 were not affected. Adenosine’s effects were phenocopied by cAMP. Specific cAMP analogs for EPAC and PKA pathways indicated that adenosine activates both intracellular cAMP receptors to inhibit dendritic cell activation. Antiinflammatory cFOS and NR4A receptor family expressions were increased by adenosine or EPAC and PKA specific cAMP analogs. Furthermore, T cells incubated with the medium of dendritic cells, which prestimulated with adenosine receptor agonist and PKAEPAC specific cAMP analogs, produced less IFNγ. Overall our data suggest that dendritic cells are regulated by adenosine through both PKA and EPAC pathways and increased the expression of NR4A nuclear orphan receptors and cFOS. Our findings suggest that for effective targeting of adenosine or other cAMP-inducing receptors both PKA and EPAC are important to modulate immune responses