A3 Receptors are Overexpressed in Pleura from Mesothelioma Patients and Reduce Cell Growth via Akt/NF-kB Pathway.

RATIONALE: A strong link has been established between exposure to asbestos and increased risk for pleural malignant mesothelioma (MM). Adenosine plays a key role in inflammatory processes and cancer where it is involved in the regulation of cell death and proliferation. OBJECTIVES: The primary aim of this study was to investigate the presence of adenosine receptors (ARs) in human MM pleura (MMP) and healthy mesothelial pleura (HMP). To shed some light on the interaction between adenosine and MM, the presence and functionality of ARs were explored in human healthy mesothelial cells (HMC) and in malignant mesothelioma cells (MMC). METHODS: ARs were analyzed by using RT-PCR, western blotting and saturation binding assays. HMC were treated with crocidolite asbestos, which is the principal risk factor of MM. The role of A3ARs on these cellular models, evaluating cAMP production, Akt phosphorylation and NF-kB activation was investigated. The dual effect of A3AR stimulation on healthy and cancer cell growth was studied by means of proliferation, apoptosis and cytotoxicity assays. MEASUREMENTS AND MAIN RESULTS: A3AR was up-regulated by 2.5 fold (P<0.01) in MMP when compared with HMP. Stimulation of A3ARs decreased proliferation and exerted a cytotoxic and pro-apoptotic effect on MMC and on HMC exposed to asbestos and TNF-α, but not on HMC with an involvement of the de-regulation of Akt/NF-kB cell survival pathway. CONCLUSION: These new findings suggest that A3AR could represent a pharmacological target to prevent tumor development after asbestos exposure and to treat full blown MM.