ADORA1 inhibition suppresses colon cancer development via hippo tumor suppressor pathway.

Coffee is one of the most commonly consumed beverages in daily life, with caffeine being the major psychoactive component that acts against fatigue and drowsiness. Epidemiological studies have demonstrated the protective effect of coffee intake on colon cancer risk, recurrence and overall survival, but the detailed mechanisms are unclear. In this study, we identified an adenosine receptor (ADORA) as an important upstream receptor for the Hippo/YAP axis and found that caffeine competitively blocked the activation of ADORA, which subsequently inhibited colon cancer carcinogenesis and progression. Caffeine blocked the activation of ADORA1 and then promoted YAP phosphorylation and deactivation via the Gαi-cAMP/PKA-LATS axis. Interestingly, YAP could bind to the promoter region of ADORA1 and facilitate its transcription, resulting in the formation of a positive feedback loop between Hippo signalling and the adenosine receptor pathway. Our study revealed a novel positive feedback loop between the Hippo/YAP axis and adenosine signalling in colon cancer progression, while the tumour-suppressive function of caffeine provides more guidance for lifestyle intervention for cancer prevention and therapeutics.