Short- and long-term (trophic) purinergic signaling in human has been studied in both normal and disease conditions, including in cancers. One of purinergic compounds, adenosine, was shown to signal through its receptors on the cell membrane. In addition, adenosine was reported to be transported into cytoplasm via equilibrative nucleoside transporters.
Cholangiocarcinoma (CCA) is a lethal disease with increasing incidence worldwide. Previous study showed that CCA was sensitive to adenosine. Thereby, molecular mechanisms of CCA inhibition by adenosine were examined in this study. Our results showed that adenosine inhibited CCA cells via an uptake of adenosine through equilibrative nucleoside transporters (ENTs), instead of activation of adenosine receptors. The inhibition of ENTs by NBTI caused the inhibitory effect of adenosine to subside, while adenosine receptor antagonists, caffeine and CGS-15943, failed to do so. Intracellular adenosine level was increased after adenosine treatment. Also, a conversion of adenosine to AMP by adenosine kinase is required in this inhibition. On the other hand, inosine, which is a metabolic product of adenosine has very little inhibitory effect on CCA cells. This indicates that a conversion of adenosine to inosine may reduce adenosine inhibitory effect. Furthermore, there was no specific correlation between level of proinflammatory proteins and CCA responses to adenosine. A metabolic stable analog of adenosine, 2Cl-adenosine, exerted higher inhibition on CCA cell growth. The disturbance in intracellular AMP level also led to an activation of 5′ AMP-activated protein kinase (AMPK). Accordingly, we proposed a novel adenosine-mediated cancer cell growth and invasion suppression via a receptor-independent mechanism in CCA.
Adenosine inhibited CCA cell growth and motility in a receptor-independent but ENT-dependent mechanism. The treatment led to an increased intracellular adenosine level, which was further changed to AMP by the activity of adenosine kinase. This conversion of adenosine to AMP is required for the inhibition. This led to an activation of AMPK. Our study provided a novel mechanism underlying CCA cell suppression by adenosine, indicating the therapeutic potential of adenosine for CCA.
This study was supported by RD&E funding (SCH-NR2015-871) from National Science and Technology Development Agency, Thailand, and the CIF grant, Faculty of Science, Mahidol University, Thailand.
|Asst. Prof. Kornkamon Lertsuwan