Zhou Qiong, Liu Ling-Zhi, Fu Beibei, Hu Xiaowen, Shi Xianglin, Fang Jing, Jiang Bing-Hua
The Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Carcinogenesis. 2007 Jan;28(1):28-37. doi: 10.1093/carcin/bgl085. Epub 2006 Jun 13.
Vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF-1) are important regulators of angiogenesis. HIF-1 is composed of HIF-1alpha and HIF-1beta subunits, and regulates VEGF expression at transcriptional level. In this study, we demonstrated that insulin induced H2O2 production and p70S6K1 activation in PC-3 prostate cancer cells. The inhibition of H2O2 production by catalase abolished insulin-induced p70S6K1 activation. H2O2 production is also required for insulin-induced VEGF and HIF-1alpha expression in the cells. Over-expression of p70S6K1 or HIF-1alpha reversed catalase- and rapamycin-inhibited VEGF transcriptional activation. These results suggest that insulin induced HIF-1alpha and VEGF expression through H2O2 production and p70S6K1 activation in prostate cancer cells. In addition, we found that inhibition of p70S6K1 by rapamycin decreased prostate tumor angiogenesis, suggesting that p70S6K1 plays an important role in tumor angiogenesis. These results provide some useful information for prostate cancer therapy in the future.
血管内皮生长因子（VEGF）和缺氧诱导因子1（HIF-1）是血管生成的重要调节因子。HIF-1由HIF-1α和HIF-1β亚基组成，并在转录水平调节VEGF表达。在本研究中，我们证明胰岛素可诱导PC-3前列腺癌细胞产生H2O2并激活p70S6K1。过氧化氢酶对H2O2产生的抑制作用消除了胰岛素诱导的p70S6K1激活。细胞中胰岛素诱导的VEGF和HIF-1α表达也需要H2O2的产生。p70S6K1或HIF-1α的过表达逆转了过氧化氢酶和雷帕霉素抑制的VEGF转录激活。这些结果表明，胰岛素通过在前列腺癌细胞中产生H2O2和激活p70S6K1来诱导HIF-1α和VEGF表达。此外，我们发现雷帕霉素对p70S6K1的抑制作用可减少前列腺肿瘤血管生成，这表明p70S6K1在肿瘤血管生成中起重要作用。这些结果为未来前列腺癌的治疗提供了一些有用的信息。
