Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara, Ferrara, Italy.
Am J Respir Crit Care Med. 2011 Feb 15;183(4):522-30. doi: 10.1164/rccm.201006-0980OC. Epub 2010 Sep 24.
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.
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).
ARs were analyzed by using reverse transcriptase-polymerase chain reaction, Western blotting, and saturation binding assays. HMC were treated with crocidolite asbestos, which is the principal risk factor for MM. The role of A₃ ARs on these cellular models, evaluating cAMP production, Akt phosphorylation, and nuclear factor (NF)-κB 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.
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 proapoptotic effect on MMC and on HMC exposed to asbestos and tumor necrosis factor-α, but not on HMC with an involvement of the deregulation of Akt/NF-κB cell survival pathway.
These new findings suggest that A₃AR could represent a pharmacological target to prevent tumor development after asbestos exposure and to treat full-blown MM.
石棉暴露与胸膜恶性间皮瘤（MM）风险增加之间存在很强的关联。腺苷在炎症过程和癌症中发挥关键作用，参与细胞死亡和增殖的调节。
本研究的主要目的是研究人类 MM 胸膜（MMP）和健康间皮胸膜（HMP）中是否存在腺苷受体（AR）。为了阐明腺苷与 MM 之间的相互作用，研究了 AR 在人健康间皮细胞（HMC）和恶性间皮瘤细胞（MMC）中的存在和功能。
通过逆转录-聚合酶链反应、Western blot 和饱和结合测定分析 AR。用青石棉处理 HMC，青石棉是 MM 的主要危险因素。研究了 A₃ AR 在这些细胞模型中的作用，评估 cAMP 产生、Akt 磷酸化和核因子（NF）-κB 激活。通过增殖、凋亡和细胞毒性测定研究 A₃AR 刺激对健康和癌细胞生长的双重影响。
与 HMP 相比，MMP 中的 A₃AR 上调了 2.5 倍（P < 0.01）。A₃AR 的刺激可降低增殖，并对 MMC 和暴露于石棉和肿瘤坏死因子-α的 HMC 产生细胞毒性和促凋亡作用，但对涉及 Akt/NF-κB 细胞存活途径失调的 HMC 没有作用。
这些新发现表明，A₃AR 可能成为预防石棉暴露后肿瘤发展和治疗完全 MM 的药理学靶点。
