Fishman Pnina, Bar-Yehuda Sara, Ardon Eti, Rath-Wolfson Lea, Barrer Faina, Ochaion Avivit, Madi Lea
Can-Fite Biopharma Ltd, Kiryat-Matalon, Laboratory of Clinical and Tumor Immunology, Felsenstein Medical Research Center, Tel-Aviv University Sackler Faculty of Medicine, Rabin Medical Center, Petach-Tikva, Israel.
Anticancer Res. 2003 May-Jun;23(3A):2077-83.
Agonists to A3 adenosine receptor (A3AR) were shown to inhibit the growth of various tumor cell types. The present study demonstrates that a synthetic A3AR agonist, 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purine- 9-yl]-N-methyl-beta-D-ribofura-nuronamide (IB-MECA), inhibits the growth of androgen-independent PC-3 prostate human carcinoma cells and illustrates the molecular mechanism involved.
PC-3 prostate carcinoma cells were used. Cell growth was examined in vitro by the thymidine incorporation assay and in vivo by inoculating the tumor cells subcutaneously into nude mice and monitoring tumor size. The protein expression level in cells and tumor extracts was tested by Western blot analysis.
A decrease in the protein expression level of A3AR and the downstream effector PKAc was observed. Consequently, the GSK-3 beta protein level increased, resulting in the destabilization of beta-catenin and the subsequent suppression of cyclin D1 and c-myc expression. IB-MECA treatment also induced down-modulation of the expression of NF-kappa B/p65, known to regulate the transcription of cyclin D1 and c-Myc. This chain of events occurred both in vitro and in vivo and suggests the use of the above-mentioned signaling proteins as markers to predict tumor cell response to A3AR activation.
Taken together, we demonstrated that A3AR activation deregulates the Wnt and the NF-kappa B signaling pathways resulting in the inhibition of prostate carcinoma cell growth.
A3 腺苷受体（A3AR）激动剂已被证明可抑制多种肿瘤细胞类型的生长。本研究表明，一种合成的 A3AR 激动剂 1-脱氧-1-[6-[[(3-碘苯基)甲基]氨基]-9H-嘌呤-9-基]-N-甲基-β-D-呋喃核糖酰胺（IB-MECA）可抑制雄激素非依赖性 PC-3 人前列腺癌细胞的生长，并阐明了其中涉及的分子机制。
使用 PC-3 前列腺癌细胞。通过胸苷掺入试验在体外检测细胞生长，并通过将肿瘤细胞皮下接种到裸鼠体内并监测肿瘤大小在体内检测细胞生长。通过蛋白质印迹分析检测细胞和肿瘤提取物中的蛋白质表达水平。
观察到 A3AR 和下游效应器 PKAc 的蛋白质表达水平降低。因此，GSK-3β 蛋白水平升高，导致 β-连环蛋白不稳定，随后细胞周期蛋白 D1 和 c-myc 表达受到抑制。IB-MECA 处理还诱导了已知可调节细胞周期蛋白 D1 和 c-Myc 转录的 NF-κB/p65 表达的下调。这一系列事件在体外和体内均发生，提示可将上述信号蛋白用作预测肿瘤细胞对 A3AR 激活反应的标志物。
综上所述，我们证明 A3AR 激活会破坏 Wnt 和 NF-κB 信号通路，从而抑制前列腺癌细胞的生长。
