Liu Ling-Zhi, Hu Xiao-Wen, Xia Chang, He Jie, Zhou Qiong, Shi Xianglin, Fang Jing, Jiang Bing-Hua
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Free Radic Biol Med. 2006 Nov 15;41(10):1521-33. doi: 10.1016/j.freeradbiomed.2006.08.003. Epub 2006 Aug 7.
The epidermal growth factor (EGF) and EGF receptor (EGFR) family are often overexpressed in various human cancers including ovarian cancer. While it is generally believed that reactive oxygen species (ROS) are involved in the intracellular signaling events, the role of ROS in EGF-induced angiogenesis and carcinogenesis remains to be elucidated. The present study investigated the role of ROS in the regulation of AKT, p70S6K1, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor 1 (HIF-1) in ovarian cancer cells. In this study, OVCAR-3 cells were treated with EGF and catalase, an H2O2 scavenger. EGF treatment increases H2O2 production, leading to activation of the AKT/p70S6K1 pathway, resulting in increased VEGF expression at the transcriptional level. The inhibition of H(2)O(2) production by catalase abolished EGF-induced AKT and p70S6K1 activation, and VEGF expression through HIF-1alpha expression. Forced expression of p70S6K1 and HIF-1alpha reversed catalase- and rapamycin-inhibited VEGF transcriptional activation. We also showed that rapamycin, p70S6K1 inhibitor and catalase overexpression inhibited tumor angiogenesis. This study demonstrates a novel mechanism of EGF-induced VEGF and HIF-1alpha expression through production of H2O2 and activation of AKT and p70S6K1 in human ovarian cancer cells. This study also indicates that p70S6K1 and H2O2 are important in tumor angiogenesis. The results of the study could have an important implication in ovarian cancer therapy.
表皮生长因子（EGF）和表皮生长因子受体（EGFR）家族在包括卵巢癌在内的多种人类癌症中常常过度表达。虽然人们普遍认为活性氧（ROS）参与细胞内信号转导事件，但ROS在EGF诱导的血管生成和致癌作用中的作用仍有待阐明。本研究调查了ROS在卵巢癌细胞中对AKT、p70S6K1、血管内皮生长因子（VEGF）和缺氧诱导因子1（HIF-1）调控中的作用。在本研究中，用EGF和过氧化氢酶（一种H2O2清除剂）处理OVCAR-3细胞。EGF处理增加了H2O2的产生，导致AKT/p70S6K1途径激活，从而在转录水平上增加VEGF表达。过氧化氢酶对H2O2产生的抑制消除了EGF诱导的AKT和p70S6K1激活以及通过HIF-1α表达的VEGF表达。p70S6K1和HIF-1α的强制表达逆转了过氧化氢酶和雷帕霉素抑制的VEGF转录激活。我们还表明，雷帕霉素、p70S6K1抑制剂和过氧化氢酶过表达抑制肿瘤血管生成。本研究证明了在人卵巢癌细胞中，EGF通过产生H2O2以及激活AKT和p70S6K1诱导VEGF和HIF-1α表达的新机制。本研究还表明p70S6K1和H2O2在肿瘤血管生成中很重要。该研究结果可能对卵巢癌治疗具有重要意义。
