TBK1 mediated regulation of E2F1 as a therapeutic target in non-small cell lung cancer

TBK1 介导的 E2F1 调节作为非小细胞肺癌的治疗靶点

• 批准号: 8881670
• 负责人: SRIKUMAR P. CHELLAPPAN
• 金额: $ 21.99万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-27 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881670
• 关键词: Accounting; Affect; Apoptosis; Attention; BIRC4 gene; Binding; Cancer Patient; Cause of Death; Cell Proliferation; Cell Survival; Cell division; Cells; Chemotherapy-Oncologic Procedure; Chronic Obstructive Airway Disease; Complex; Diagnosis; Diagnostic Neoplasm Staging; Disease; Drug resistance; E2F Transcription Factor 1; E2F1 gene; Epidermal Growth Factor Receptor; Event; Exposure to; Genes; Genetic Transcription; Growth; Human; IRF3 gene; Immune; Inflammation; Inflammatory; Invaded; KRAS2 gene; Light; MMP9 gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Molecular; Mus; Mutation; NF-kappa B; Natural Immunity; Neoplasm Metastasis; Nicotine; Nicotinic Receptors; Nitrosamines; Non-Small-Cell Lung Carcinoma; Oncogenic; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Proteins; RAS genes; Reaction; Regulation; Regulatory Pathway; Reporting; Resistance; Role; Sampling; Signal Transduction; Smoker; Smoking; Survival Rate; TLR4 gene; TP53 gene; Tobacco; Tobacco smoke; Tobacco use; United States; Xenograft procedure; angiogenesis; base; cancer cell; chemotherapeutic agent; combat; cytokine; environmental tobacco smoke exposure; human MMP14 protein; in vivo; inhibitor/antagonist; innovation; migration; mortality; mutant; non-smoker; novel; novel therapeutics; outcome forecast; prevent; promoter; public health relevance; receptor; receptor-mediated signaling; research study; response; small molecule; survivin; therapeutic target; tumor; tumor growth; tumorigenesis

 DESCRIPTION (provided by applicant): TBK1 (Tank Binding Kinase 1) plays a major role in mediating innate immunity and is a known regulator of NF kB mediated transcriptional regulatory pathway. TBK1 activates survival pathways mediated by NFkB, and is an important downstream mediator of K-Ras-dependent oncogenic events. Recent studies have shown that the RalB signaling module and the exocyst complex activate TBK1 and promote survival of K-Ras mutant cancer cells through direct phosphorylation of Akt. Our earlier studies had shown that exposure of cells to nicotine, the addictive component of tobacco smoke, activates Akt and stabilizes XIAP, rendering non-small cell lung cancer (NSCLC) cells resistant to apoptosis induced by chemotherapeutic agents. This survival mechanism is also involved in induction of E2F1-mediated transcriptional activity, resulting in elevated expression of survivin. We had also found that nicotine could promote the growth and metastasis of NSCLC in mice, and could induce the expression of multiple matrix metalloproteinases including MMP9, MMP14 and MMP15 in an E2F1-dependent manner. A disruptor of the Rb-Raf-1 interaction, which inhibits the transcriptional activity of E2F1, could inhibit the expression of MMPs and prevent cell invasion, migration and metastasis in mice. Interestingly, our recent studies show that exposure of cells to nicotine activates TBK1 and facilitates nicotine-mediated cell proliferation. Levels of active phospho-TBK1 are elevated in human tumor samples as well as in tumors from mice that are exposed to nicotine. Further, TBK1 physically interacts with E2F1 transcription factor and phosphorylates it efficiently, enhancing E2F1-mediated transcription. TBK1 could also induce MMP promoters in an E2F1-dependent fashion, and depletion of TBK1 reduces the endogenous levels of MMP9 and 14. Based on these observations, we hypothesize that TBK1 is a vital downstream target of K-Ras as well as nicotinic acetylcholine receptor (nAChR)-mediated signaling and it facilitates the progression and metastasis of lung cancer through E2F1 regulation. Based on this hypothesis, we propose that the combination of small molecule inhibitors of TBK1 and E2F1 would be highly efficient in inhibiting the growth and metastasis of non-small cell lung cancers. We believe that these studies are highly innovative and will have a significant impact on our efforts to combat non-small cell lung cancer.

 描述（由适用提供）：TBK1（储罐结合激酶1）在介导先天免疫力中起主要作用，并且是NF KB介导的转录调节途径的已知调节剂。 TBK1激活NFKB介导的生存途径，是K-RAS依赖性致癌事件的重要下游介体。最近的研究表明，Ralb信号传导模块和胞外复合物通过直接磷酸化AKT激活TBK1并促进K-RAS突变癌细胞的存活。我们的早期研究表明，细胞暴露于尼古丁（烟草烟雾的附加成分），激活AKT并稳定XIAP，从而使非小细胞肺癌（NSCLC）细胞抗化学治疗剂诱导的凋亡。这种生存机制还参与了E2F1介导的转录活性的诱导，从而导致Survivin的表达升高。我们还发现，尼古丁可以在小鼠中促进NSCLC的生长和转移，并可以以E2F1依赖性方式诱导多种基质金属蛋白酶的表达。抑制E2F1转录活性的RB-RAF-1相互作用的破坏者可以抑制MMP的表达并防止小鼠的细胞侵袭，迁移和转移。有趣的是，我们最近的研究表明，细胞暴露于尼古丁会激活TBK1并促进尼古丁介导的细胞增殖。水平 活性磷酸-TBK1在人类肿瘤样品以及暴露于尼古丁的小鼠的肿瘤中升高。此外，TBK1与E2F1转录因子物理相互作用并有效地磷酸化，从而增强了E2F1介导的转录。 TBK1 could also induce MMP promoters in an E2F1-dependent fashion, and depletion of TBK1 reduces the endogenous levels of MMP9 and 14. Based on these observations, we hypothesize that TBK1 is a vital downstream target of K-Ras as well as nicotinic acetylcholine receptor (nAChR)-mediated signaling and it facilitates the progression and metastasis通过E2F1调节的肺癌。基于这一假设，我们提出，TBK1和E2F1的小分子抑制剂的组合将在抑制非小细胞肺癌的生长和转移方面高效。我们认为，这些研究具有很高的创新性，将对我们打击非小细胞肺癌的努力产生重大影响。