Microtubule-targeting and regulation of HIF-1

描述（由申请人提供）： 2-甲氧基雌二醇（2ME 2）是雌二醇的天然衍生物，目前作为肿瘤血管生成的抑制剂处于I/II期临床试验中。我们最近报道，2ME2有效地抑制促血管生成和促存活转录因子HIF-1 α的蛋白水平和转录活性。此外，我们发现HIF-1 α抑制发生在2ME 2破坏微管细胞骨架的下游。这些数据提供了微管细胞骨架靶向和肿瘤血管生成抑制之间的第一个机制联系。然而，从微管破坏到HIF-1 α抑制的细胞信号仍然未知。 有了这个建议，我们试图建立在我们以前的工作，以详细调查的分子机制，导致从微管破坏抑制肿瘤血管生成和生存。我们的假设是2ME 2对微管依赖性HIF-1 α激活的化学机制具有二价作用。通过破坏细胞微管，2ME 2抑制HIF-1 α核转位和HIF-1 α翻译，从而导致HIF-1 α活性的抑制。为了阐明微管破坏调节HIF-1 α活性的机制，我们计划：I）阐明2ME 2抑制HIF-1核转位的机制，II）确定2ME 2抑制HIF-1 α翻译的机制，III）研究VHL突变型肾细胞癌（RCC）中HIF-1 α微管依赖性调节的消除是否导致2ME 2耐药。我们还将这些观察扩展到其他类别的微管靶向药物，如紫杉烷，埃博霉素和长春花生物碱。有了这个建议，我们正在寻求建立在我们以前的工作，并推进我们的理解的基本机制，微管依赖性调节HIF途径，以及它们对肿瘤生存和化疗敏感性的影响。

DESCRIPTION (provided by applicant): 2-Methoxyestradiol (2ME2) is a naturally occurring derivative of estradiol currently in Phase l/ll clinical trials as an inhibitor of tumor angiogenesis. We have recently reported that 2ME2 potently inhibits the protein levels and transcriptional activity of the pro-angiogenic and pro-survival transcription factor HIF-1 alpha. Moreover, we showed that HIF-1 alpha inhibition occurs downstream of disruption of the microtubule cytoskeleton by 2ME2. These data provide the first mechanistic link between targeting of the microtubule cytoskeleton and inhibition of tumor angiogenesis. However, the cellular signals that lead from microtubule disruption to HIF-1 alpha inhibition remain unknown. With this proposal, we seek to build upon our previous work in order to investigate in detail the molecular mechanism(s) that lead from microtubule disruption to inhibition of tumor angiogenesis and survival. Our hypothesis is that 2ME2 has a bivalent effect on the chemomechanics of microtubule-dependent HIF-1 alpha activation. By disrupting cellular microtubules, 2ME2 inhibits HIF-1 alpha nuclear translocation and HIF-1 alpha translation, thus, resulting in inhibition of HIF-1 alpha activity. To elucidate the mechanism by which microtubule disruption regulates HIF-1 alpha activity we plan to: I) Elucidate the mechanism by which 2ME2 inhibits HIF-1 nuclear translocation, II) Define the mechanism by which 2ME2 inhibits HIF-1 alpha translation and III) Investigate whether abrogation of microtubule-dependent regulation of HIF-1 alpha in VHL-mutant renal cell carcinomas (RCCs), results in 2ME2 resistance. We will also expand these observations to additional classes of microtubule-targeting drugs, such as the taxanes, the epothilones and the vinca alkaloids. With this proposal we are seeking to build on our previous work and advance our understanding of the basic mechanisms governing the microtubule-dependent regulation of the HIF pathway, as well as their impact on tumor survival and chemosensitivity.