Mabjeesh Nicola J, Escuin Daniel, LaVallee Theresa M, Pribluda Victor S, Swartz Glenn M, Johnson Michelle S, Willard Margaret T, Zhong Hua, Simons Jonathan W, Giannakakou Paraskevi
Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Cancer Cell. 2003 Apr;3(4):363-75. doi: 10.1016/s1535-6108(03)00077-1.
Inhibition of angiogenesis is an important new modality for cancer treatment. 2-methoxyestradiol (2ME2) is a novel antitumor and antiangiogenic agent, currently in clinical trials, whose molecular mechanism of action remains unclear. Herein, we report that 2ME2 inhibits tumor growth and angiogenesis at concentrations that efficiently disrupt tumor microtubules (MTs) in vivo. Mechanistically, we found that 2ME2 downregulates hypoxia-inducible factor-1 (HIF) at the posttranscriptional level and inhibits HIF-1-induced transcriptional activation of VEGF expression. Inhibition of HIF-1 occurs downstream of the 2ME2/tubulin interaction, as disruption of interphase MTs is required for HIF-alpha downregulation. These data establish 2ME2 as a small molecule inhibitor of HIF-1 and provide a mechanistic link between the disruption of the MT cytoskeleton and inhibition of angiogenesis.
抑制血管生成是癌症治疗的一种重要新方法。2-甲氧基雌二醇（2ME2）是一种新型抗肿瘤和抗血管生成药物，目前正处于临床试验阶段，其分子作用机制尚不清楚。在此，我们报告2ME2在体内有效破坏肿瘤微管（MTs）的浓度下可抑制肿瘤生长和血管生成。从机制上讲，我们发现2ME2在转录后水平下调缺氧诱导因子-1（HIF），并抑制HIF-1诱导的VEGF表达的转录激活。HIF-1的抑制发生在2ME2/微管蛋白相互作用的下游，因为HIF-α的下调需要破坏间期微管。这些数据确立了2ME2作为HIF-1的小分子抑制剂，并提供了微管细胞骨架破坏与血管生成抑制之间的机制联系。
