Innovative Drug Research Center for Metabolic and Inflammatory Diseases, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, Korea.
Mol Cancer Ther. 2009 Oct;8(10):2791-802. doi: 10.1158/1535-7163.MCT-09-0420. Epub 2009 Sep 29.
Hypoxia-inducible factor-1alpha (HIF-1alpha) induces tumor proliferation, angiogenesis and metastasis. Reactive oxygen species, hypoxia, and growth factor stimulation induce HIF-1alpha, and the augmented HIF-1alpha activity confers upon cancer cells the ability to adapt to microenvironments. Oltipraz is a cancer chemopreventive agent and has an inhibitory effect on angiogenesis and tumor growth. Nonetheless, the molecular mechanism of tumor inhibition is as yet unclear. This study investigated whether oltipraz and its congeners inhibit HIF-1alpha activity and, if so, the molecular basis of inhibition. Oltipraz and other 1,2-dithiole-3-thiones have the ability to prevent insulin- or hypoxia-induced HIF-1alpha expression through an increase in ubiquitination, thereby accelerating HIF-1alpha degradation and inhibiting HIF-1alpha-dependent gene transcription. Transfection of cells with a constitutively active mutant of p70 ribosomal S6 kinase-1 (CA-S6K1) increased the basal and insulin-inducible HIF-1alpha activity. CA-S6K1 overexpression reversed HIF-1alpha inhibition by rapamycin (a mammalian target of rapamycin/S6K1 inhibitor). However, the inhibitory effect of oltipraz on HIF-1alpha was not reversed by CA-S6K1 despite its S6K1 inhibition. The failure of dominant negative mutant AMP-activated protein kinase-alpha to restore the ability of insulin to increase HIF-1alpha against oltipraz excluded the possible role of AMP-activated protein kinase activation in the action of oltipraz. Oltipraz treatment abrogated insulin-induced H(2)O(2) production, thereby preventing H(2)O(2)-enhanced HIF-1alpha expression and promoting its ubiquitination and degradation. In an animal model, tumor regression by oltipraz was accompanied by decreases in microvessel density and vascular endothelial growth factor induction. Oltipraz inhibits HIF-1alpha activity and HIF-1alpha-dependent tumor growth, which may result from a decrease in HIF-1alpha stability through S6K1 inhibition in combination with an H(2)O(2)-scavenging effect.
缺氧诱导因子-1α（HIF-1α）可诱导肿瘤增殖、血管生成和转移。活性氧、缺氧和生长因子刺激诱导 HIF-1α，增强的 HIF-1α 活性使癌细胞能够适应微环境。奥替普拉是一种癌症化学预防剂，具有抑制血管生成和肿瘤生长的作用。然而，肿瘤抑制的分子机制尚不清楚。本研究探讨了奥替普拉及其同系物是否抑制 HIF-1α 活性，如果是，抑制的分子基础是什么。奥替普拉和其他 1,2-二硫杂环戊烯-3-硫酮能够通过增加泛素化来防止胰岛素或缺氧诱导的 HIF-1α 表达，从而加速 HIF-1α 降解并抑制 HIF-1α 依赖性基因转录。用组成型激活的核糖体 S6 激酶-1（CA-S6K1）转染细胞会增加基础和胰岛素诱导的 HIF-1α 活性。CA-S6K1 过表达逆转了雷帕霉素（哺乳动物雷帕霉素靶蛋白/S6K1 抑制剂）对 HIF-1α 的抑制作用。然而，奥替普拉对 HIF-1α 的抑制作用并没有被 CA-S6K1 逆转，尽管 S6K1 被抑制。显性负突变 AMP 激活蛋白激酶-α不能恢复胰岛素增加 HIF-1α 的能力，这排除了 AMP 激活蛋白激酶激活在奥替普拉作用中的可能作用。奥替普拉处理消除了胰岛素诱导的 H2O2 产生，从而防止了 H2O2 增强的 HIF-1α 表达，并促进了其泛素化和降解。在动物模型中，奥替普拉引起的肿瘤消退伴随着微血管密度和血管内皮生长因子诱导的减少。奥替普拉抑制 HIF-1α 活性和 HIF-1α 依赖性肿瘤生长，这可能是由于 S6K1 抑制与 H2O2 清除作用相结合，降低了 HIF-1α 的稳定性所致。
