Merighi Stefania, Benini Annalisa, Mirandola Prisco, Gessi Stefania, Varani Katia, Leung Edward, Maclennan Stephen, Borea Pier Andrea
Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara, 44100 Ferrara, Italy.
Biochem Pharmacol. 2006 Jun 28;72(1):19-31. doi: 10.1016/j.bcp.2006.03.020. Epub 2006 Mar 29.
Hypoxia appears to induce a program which shifts the cellular phenotype toward an increase in extracellular adenosine. Hypoxia-inducible factor-1 (HIF-1) is a key regulator of genes crucial to many aspects of cancer biology. Since in gliomas there is a strong correlation between HIF-1alpha expression, tumor grade and tumor vascularization, the aim of this study was to investigate whether adenosine may regulate HIF-1 in human glioblastoma cell lines. The results indicate that in the human hypoxic A172 and U87MG glioblastoma cell lines adenosine up-regulates HIF-1alpha protein expression via the A(3) receptor subtype. In particular, we investigated the effect of A(3) receptor antagonists on HIF-1 and vascular endothelial growth factor (VEGF) expression. We found that A(3) antagonists inhibit adenosine-induced HIF-1alpha and VEGF protein accumulation in the hypoxic cells. Investigations in the molecular mechanism showed that A(3) receptor stimulation activates p44/p42 and p38 MAPKs that are required for A(3)-induced increase of HIF-1alpha and VEGF. Further studies are required to demonstrate the in vivo relevance of these observations with regard to the proposed role for adenosine as a key element in hypoxia and in tumors.
缺氧似乎会诱导一种程序，使细胞表型向细胞外腺苷增加的方向转变。缺氧诱导因子-1（HIF-1）是对癌症生物学许多方面至关重要的基因的关键调节因子。由于在胶质瘤中，HIF-1α表达、肿瘤分级和肿瘤血管生成之间存在很强的相关性，本研究的目的是调查腺苷是否可能调节人胶质母细胞瘤细胞系中的HIF-1。结果表明，在人缺氧A172和U87MG胶质母细胞瘤细胞系中，腺苷通过A(3)受体亚型上调HIF-1α蛋白表达。具体而言，我们研究了A(3)受体拮抗剂对HIF-1和血管内皮生长因子（VEGF）表达的影响。我们发现A(3)拮抗剂抑制缺氧细胞中腺苷诱导的HIF-1α和VEGF蛋白积累。分子机制研究表明，A(3)受体刺激激活p44/p42和p38 MAPK，这是A(3)诱导的HIF-1α和VEGF增加所必需的。需要进一步研究来证明这些观察结果在体内与腺苷作为缺氧和肿瘤中的关键元素所提出的作用的相关性。
