Ras-Induced Lung Cancer: Key Roles for IKK and NF-kappaB

Ras 诱导的肺癌：IKK 和 NF-kappaB 的关键作用

基本信息

批准号：
8606415
负责人：
ALBERT Sidney BALDWIN
金额：
$ 24.48万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8606415
关键词：
Animal Cancer Model Animal Model Animals Apoptosis Cancer Patient Cell Death Cell Death Induction Cells Complex Data Dominant-Negative Mutation Epithelial Cells Event Family member Foundations Frequencies Gene Expression Genes Genetic Engineering Glycogen Synthase Kinase 3 HRAS gene Human In Vitro Individual Induction of Apoptosis Lead Link Lung Lung Neoplasms Maintenance Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Modeling Molecular Mutate Mutation NF-kappa B Neoplasm Metastasis Nuclear Oncogenes Oncogenic Outcome Pancreas Pathway interactions Pharmaceutical Preparations Phenotype Phosphotransferases Protein Isoforms Proteins Proto-Oncogenes Publishing Regulation Relative (related person)Reporting Research Resistance Role Signal Pathway Signal Transduction TBK1 gene Testing Therapeutic Therapeutic Intervention Therapeutic Studies Tumor Suppression Variant Work aurora B kinase aurora kinase aurora-A kinase base bcr-abl Fusion Proteins cancer cell cancer therapy cell transformation human STK6 protein improved in vivo inhibitor/antagonist insight kinase inhibitor lung tumorigenesis mutant neoplastic cell new therapeutic target outcome forecast p65 pre-clinical public health relevance ras Proteins research study response therapeutic target transcription factor tumor tumor growth tumor initiation tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Oncogenic mutations in Ras proteins lead to transforming potential in a number of epithelial cells. Unfortunately, the ability to suppress the Ras-driven signaling pathway in tumors, to date, has largely been unsuccessful. We originally showed that the transcription factor NF-?B is important for Ras-induced cell transformation through its ability to suppress Ras-induced cell death. In the first in vivo test for a role of NF-?B in oncogene-induced tumorigenesis, we show here that loss of the gene encoding the RelA/p65 NF-?B subunit suppresses Ras-induced tumorigenesis in a lung tumor model. Importantly, loss of RelA/p65 leads to apoptosis in these Ras-transformed cells. In vitro data indicate that IKKa and ¿, upstream regulators of NF-?B, and Aurora kinase control the ability of oncogenic Ras mutants to activate NF-?B. Additional new data indicate that variant forms of IKK, namely TBK1 and IKKe, nuclear in human lung tumor cells and that a dominant negative form of IKKe blocks NF-kB activation in these cells. Work from Counter and colleagues shows that the PI3K/Akt pathway is critical for tumor maintenance in a Ras-induced setting. We provide preliminary data that IKKa, in a manner distinct from its ability to control NF-?B activation, promotes Akt activity in cancer cells through regulation of the TORC2 complex. Due to the poor prognosis of many lung cancer patients and the hope for improved therapy of lung cancer, we have focused this proposal on K-Ras-induced lung tumorigenesis. The central hypotheses of this application are that: (1) a critical downstream effector of oncogenic K-Ras in lung cancer is the transcription factor NF-?B, (2) NF-?B activation induced by K-Ras involves therapeutic targets: Aurora kinases and I?B kinase a and ¿ (IKK¿), and potentially TBK1/IKKe and GSK-a/¿; (3) therapies targeting IKK or Aurora kinase, and potentially GSK-a/¿ will suppress tumor growth. Four specific aims are proposed to test these hypotheses. The proposed research may provide an experimental foundation leading to new treatments for Ras-positive tumors and will provide insight into molecular signaling events that are dysregulated downstream of mutant Ras expression.

描述（由适用提供）：RAS蛋白质中的致癌突变导致许多上皮细胞中的潜力转化。不幸的是，迄今为止，抑制肿瘤中RAS驱动的信号通路的能力在很大程度上没有成功。我们最初表明，转录因子NF-？b通过抑制Ras诱导的细胞死亡的能力而对RAS诱导的细胞转化很重要。在第一个在癌基因诱导的肿瘤发生中的Nf- b的体内测试中，我们在这里表明，编码RERA/p65 nf- b亚基的基因丧失抑制了肺部肿瘤模型中Ras诱导的肿瘤发生。重要的是，Rela/p65的丧失会导致这些RAS转换细胞的凋亡。体外数据表明NF-？B的上游调节剂Ikka和„和Aurora激酶控制致癌性Ras突变体激活NF-？B的能力。其他新数据表明，IKK的变体形式，即TBK1和IKKE，人类肺肿瘤细胞中的核，并且IKKE的主要负面形式阻止了这些细胞中的NF-KB激活。来自计数器和同事的工作表明，PI3K/AKT途径对于在RAS诱导的环境中维持肿瘤至关重要。我们提供了初步数据，即IKKA以与控制NF-？B激活的能力不同的方式，通过调节TORC2复合物来促进癌细胞中的AKT活性。由于许多肺癌患者的预后不良以及对肺癌治疗的希望的希望，我们将这一建议集中在K-RAS诱导的肺肿瘤上。 The central hypotheses of this application are that: (1) a critical downstream effector of oncogenic K-Ras in lung cancer is the transcription factor NF-?B, (2) NF-?B activation induced by K-Ras involves thermal targets: Aurora kinases and I?B kinase a and ¿ (IKK¿), and potentially TBK1/IKKe and GSK-a/¿ ; （3）靶向IKK或Aurora激酶以及潜在的GSK-A/»的疗法将抑制肿瘤的生长。提出了四个特定目标来检验这些假设。拟议的研究可以为RAS阳性肿瘤提供新的治疗方法，并将深入了解突变RAS表达下游失调的分子信号事件。