Adenosine receptors and cancer.
Adenosine receptors and cancer.
复制标题
DOI：
10.1007/978-3-540-89615-9_14
复制
发表时间：
2009
影响因子：
--
通讯作者：
Borea, P A
中科院分区：
文献类型：
--
作者：
Fishman, P;Bar-Yehuda, S;Synowitz, M;Powell, J D;Klotz, K N;Gessi, S;Borea, P A
发现 A1、A2A、A2B 和 A3 G 蛋白偶联细胞表面腺苷受体 (AR) 在各种肿瘤细胞中上调。特定配体、激动剂或拮抗剂激活受体，通过一系列信号传导途径调节肿瘤生长。 A1AR被发现在预防胶质母细胞瘤的发展中发挥作用。 A1AR 的这种抗肿瘤作用是通过肿瘤相关小胶质细胞介导的。 A2AAR 的激活通过抑制 T 调节细胞功能和抑制自然杀伤细胞的细胞毒性和肿瘤特异性 CD4+/CD8+ 活性来抑制肿瘤的免疫反应。因此，表明特定拮抗剂的药理抑制可能增强癌症治疗中的免疫治疗。 A2BAR 的激活通过上调微血管内皮细胞中血管生成因子的表达水平在肿瘤的发展中发挥作用。相反，A2BAR 的激活显然会抑制 ERK1/2 磷酸化和 MAP 激酶活性，而这些都参与肿瘤细胞生长信号。最后，发现 A3AR 在肿瘤细胞和组织中高表达，而在正常细胞或邻近组织中低表达。肿瘤组织中的受体表达与疾病严重程度直接相关。肿瘤中受体的高表达归因于 NF-κB 的过度表达，NF-κB 已知充当 A3AR 转录因子。有趣的是，在来自荷瘤动物和癌症患者的外周血单核细胞 (PBMC) 中发现了高 A3AR 表达水平，反映了肿瘤中的受体状态。研究发现 A3AR 激动剂通过调节 Wnt 和 NF-κB 信号通路在体外和体内诱导肿瘤生长抑制。总而言之，在肿瘤细胞中大量表达的 A3AR 可能会被特定的 A3AR 激动剂靶向，从而抑制肿瘤生长。这些 A3AR 激动剂的独特特性使它们成为有吸引力的候选药物。
The A1, A2A, A2B and A3 G-protein-coupled cell surface adenosine receptors (ARs) are found to be upregulated in various tumor cells. Activation of the receptors by specific ligands, agonists or antagonists, modulates tumor growth via a range of signaling pathways. The A1AR was found to play a role in preventing the development of glioblastomas. This antitumor effect of the A1AR is mediated via tumor-associated microglial cells. Activation of the A2AAR results in inhibition of the immune response to tumors via suppression of T regulatory cell function and inhibition of natural killer cell cytotoxicity and tumor-specific CD4+/CD8+ activity. Therefore, it is suggested that pharmacological inhibition by specific antagonists may enhance immunotherapeutics in cancer therapy. Activation of the A2BAR plays a role in the development of tumors via upregulation of the expression levels of angiogenic factors in microvascular endothelial cells. In contrast, it was evident that activation of A2BAR results in inhibition of ERK1/2 phosphorylation and MAP kinase activity, which are involved in tumor cell growth signals. Finally, A3AR was found to be highly expressed in tumor cells and tissues while low expression levels were noted in normal cells or adjacent tissue. Receptor expression in the tumor tissues was directly correlated to disease severity. The high receptor expression in the tumors was attributed to overexpression of NF-κB, known to act as an A3AR transcription factor. Interestingly, high A3AR expression levels were found in peripheral blood mononuclear cells (PBMCs) derived from tumor-bearing animals and cancer patients, reflecting receptor status in the tumors. A3AR agonists were found to induce tumor growth inhibition, both in vitro and in vivo, via modulation of the Wnt and the NF-κB signaling pathways. Taken together, A3ARs that are abundantly expressed in tumor cells may be targeted by specific A3AR agonists, leading to tumor growth inhibition. The unique characteristics of these A3AR agonists make them attractive as drug candidates.