Regulation of VEGF/HIF-1 by AKT: Implications for Radiotherapy

AKT 对 VEGF/HIF-1 的调节：对放射治疗的影响

• 批准号: 7625242
• 负责人: Amit Maity
• 金额: $ 24.92万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7625242
• 关键词: Binding; Blood Vessels; Clinic; Clinical; Consensus; Data; Down-Regulation; EGFR inhibition; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Figs - dietary; Gefitinib; Genetic Transcription; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Goals; Growth; Head and Neck Squamous Cell Carcinoma; Human; Hypoxia; Hypoxia Inducible Factor; Lead; Literature; Malignant Neoplasms; Mediating; Mediator of activation protein; Nude Mice; Oxygen Consumption; PI3K/AKT; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Site; Play; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Radiation; Radiation Tolerance; Radiation therapy; Radiosensitization; Regulation; Research Personnel; Role; Running; Secondary to; Serum; Signal Transduction; Sirolimus; Sp1 Transcription Factor; Testing; Transactivation; Translations; Tumor Oxygenation; Vascular Endothelial Growth Factors; Work; Xenograft procedure; angiogenesis; human FRAP1 protein; in vivo; inhibitor/antagonist; kinase inhibitor; mTOR Inhibitor; overexpression; programs; promoter; tissue culture; transcription factor; tumor

DESCRIPTION (provided by applicant): Our long-term goal is to determine mechanisms by which the PI3K/AKT pathway, which is commonly activated in human cancers, increases expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-la (HIF-la). We also wish to understand what role this may play in the efficacy of EGFR inhibitors, which are currently being used in the clinic. VEGF, a key mediator of angiogenesis, is often overexpressed in human cancers. Hypoxia has long been recognized to be a potent inducer of VEGF expression through the transcription factor HIF-1. We have found that the PI3K/AKT pathway plays an important role in VEGF regulation through at least two different mechanisms. First, the PI3K/AKT pathway increases transcription by increasing binding of the transcription factor Sp1 to the VEGF proximal core promoter. Secondly, the AKT pathway can increase the expression of HIF-1a, which can also lead to increased VEGF transcription, particularly in hypoxia. In Specific Aim 1 we will explore the mechanisms by which AKT leads to increased Sp1-mediated transactivation of the VEGF promoter. In Specific Aim 2 we will study the potential role of glycogen synthase kinase-3p (GSK-3J3), a downstream target of AKT involved in protein translation, on increasing HIF-1 a. A number of drugs are currently being tested in the clinic that may work in part through the mechanisms described above. EGFR inhibitors (e.g. gefitinib, erlotinib) decrease PI3K/AKT signaling and we have found that these inhibitors also decrease HIF-1a and VEGF expression. Our preliminary data suggest that gefitinib may increase tumor oxygenation, which should lead to increased radiosensitization. Therefore, in Specific Aim 3 we will study the effects of EGFR inhibition on HIF-1 a and VEGF expression and on tumor oxygenation in vivo and the effects on radiosensitivity. LAY SUMMARY: We will study how the expression of VEGF, an important mediator of blood vessel growth, is increased in human tumors. The clinical importance of these studies is that EGFR inhibitors currently being used in the clinic may work though these pathways to increase the oxygenation of tumors. Increased oxygenation should make tumors more sensitive to radiation; therefore, our studies may be important in helping to optimize the combination of EGFR inhibitors with radiation.

描述（由申请人提供）：我们的长期目标是确定在人类癌症中通常被激活的 PI3K/AKT 通路增加血管内皮生长因子 (VEGF) 和缺氧诱导因子-1a (HIF-1a) 表达的机制。我们还希望了解这对于目前临床上使用的 EGFR 抑制剂的功效可能发挥什么作用。 VEGF 是血管生成的关键介质，通常在人类癌症中过度表达。长期以来，缺氧一直被认为是通过转录因子 HIF-1 诱导 VEGF 表达的有效诱导剂。我们发现PI3K/AKT通路通过至少两种不同的机制在VEGF调节中发挥重要作用。首先，PI3K/AKT 途径通过增加转录因子 Sp1 与 VEGF 近端核心启动子的结合来增加转录。其次，AKT途径可以增加HIF-1a的表达，这也可以导致VEGF转录增加，特别是在缺氧的情况下。在具体目标 1 中，我们将探讨 AKT 导致 Sp1 介导的 VEGF 启动子反式激活增加的机制。在具体目标 2 中，我们将研究糖原合酶激酶 3p (GSK-3J3)（参与蛋白质翻译的 AKT 下游靶标）对增加 HIF-1a 的潜在作用。目前，许多药物正在临床中进行测试，这些药物可能部分通过上述机制发挥作用。 EGFR 抑制剂（例如吉非替尼、厄洛替尼）可减少 PI3K/AKT 信号转导，我们发现这些抑制剂还可减少 HIF-1a 和 VEGF 的表达。我们的初步数据表明，吉非替尼可能会增加肿瘤氧合，从而增加放射增敏作用。因此，在具体目标3中，我们将研究EGFR抑制对HIF-1a和VEGF表达以及体内肿瘤氧合的影响以及对放射敏感性的影响。简单总结：我们将研究 VEGF（血管生长的重要介质）的表达如何在人类肿瘤中增加。这些研究的临床重要性在于，目前临床上使用的 EGFR 抑制剂可能通过这些途径来增加肿瘤的氧合。氧合作用的增加会使肿瘤对辐射更加敏感；因此，我们的研究对于帮助优化 EGFR 抑制剂与放射的组合可能很重要。