Jiang B H, Jiang G, Zheng J Z, Lu Z, Hunter T, Vogt P K
Department of Molecular and Experimental Medicine, BCC239, The Scripps Research Institute, La Jolla, California 92037, USA.
Cell Growth Differ. 2001 Jul;12(7):363-9.
The phosphatidylinositol 3-kinase (PI3K) signaling pathway has inherent oncogenic potential. It is up-regulated in diverse human cancers by either a gain of function in PI3K itself or in its downstream target Akt or by a loss of function in the negative regulator PTEN. However, the complete consequences of this up-regulation are not known. Here we show that insulin and epidermal growth factor or an inactivating mutation in the tumor suppressor PTEN specifically increase the protein levels of hypoxia-inducible factor (HIF) 1alpha but not of HIF-1beta in human cancer cell lines. This specific elevation of HIF-1alpha protein expression requires PI3K signaling. In the prostate carcinoma-derived cell lines PC-3 and DU145, insulin- and epidermal growth factor-induced expression of HIF-1alpha was inhibited by the PI3K-specific inhibitors LY294002 and wortmannin in a dose-dependent manner. HIF-1beta expression was not affected by these inhibitors. Introduction of wild-type PTEN into the PTEN-negative PC-3 cell line specifically inhibited the expression of HIF-1alpha but not that of HIF-1beta. In contrast to the HIF-1alpha protein, the level of HIF-1alpha mRNA was not significantly affected by PI3K signaling. Vascular endothelial growth factor reporter gene activity was induced by insulin in PC-3 cells and was inhibited by the PI3K inhibitor LY294002 and by the coexpression of a HIF-1 dominant negative construct. Vascular endothelial growth factor reporter gene activity was also inhibited by expression of a dominant negative PI3K construct and by the tumor suppressor PTEN.
磷脂酰肌醇3激酶（PI3K）信号通路具有内在的致癌潜力。在多种人类癌症中，PI3K自身或其下游靶点Akt功能获得性改变，或负性调节因子PTEN功能缺失，均可导致该信号通路上调。然而，这种上调的完整后果尚不清楚。在此，我们发现胰岛素和表皮生长因子，或肿瘤抑制因子PTEN的失活突变，可特异性增加人类癌细胞系中缺氧诱导因子（HIF）1α的蛋白水平，但不影响HIF-1β的蛋白水平。HIF-1α蛋白表达的这种特异性升高需要PI3K信号传导。在前列腺癌衍生的细胞系PC-3和DU145中，PI3K特异性抑制剂LY294002和渥曼青霉素以剂量依赖方式抑制胰岛素和表皮生长因子诱导的HIF-1α表达。这些抑制剂不影响HIF-1β的表达。将野生型PTEN导入PTEN阴性的PC-3细胞系中，可特异性抑制HIF-1α的表达，但不影响HIF-1β的表达。与HIF-1α蛋白不同，PI3K信号传导对HIF-1α mRNA水平没有显著影响。血管内皮生长因子报告基因活性在PC-3细胞中被胰岛素诱导，并被PI3K抑制剂LY294002和HIF-1显性负性构建体的共表达所抑制。血管内皮生长因子报告基因活性也被显性负性PI3K构建体的表达和肿瘤抑制因子PTEN所抑制。
