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: 9059672
• 负责人: SRIKUMAR P. CHELLAPPAN
• 金额: $ 18.32万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9059672
• 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; E2F1 gene; Epidermal Growth Factor Receptor; Event; Exposure to; Genes; Genetic Transcription; Growth; Health; Human; IRF3 gene; Immune; Inflammation; Inflammatory; Invaded; KRAS2 gene; Light; MMP14 gene; 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; in vivo; inhibitor/antagonist; innovation; migration; mortality; mutant; non-smoker; novel; novel therapeutics; outcome forecast; overexpression; prevent; promoter; receptor; receptor-mediated signaling; research study; response; small molecule inhibitor; 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(申请人提供)：TBK1(Tank Binding Kinase 1)在调节先天免疫中起主要作用，是已知的核因子kB介导的转录调控途径的调节者。TBK1激活NFkB介导的生存通路，是K-RAS依赖的致癌事件的重要下游介体。最近的研究表明，RalB信号模块和胞外复合体通过直接磷酸化Akt来激活TBK1，促进K-RAS突变癌细胞的存活。我们早期的研究表明，细胞暴露于烟草烟雾中的成瘾成分尼古丁，激活Akt并稳定XIAP，使非小细胞肺癌(NSCLC)细胞对化疗药物诱导的凋亡产生抵抗。这一生存机制也参与了E2F1介导的转录活性的诱导，导致Survivin表达上调。我们还发现尼古丁可以促进小鼠非小细胞肺癌的生长和转移，并能以E2F1依赖的方式诱导包括MMP9、MMP14和MMP15在内的多种基质金属蛋白酶的表达。Rb-Raf-1相互作用的干扰物可以抑制E2F1的转录活性，从而抑制MMPs的表达，防止细胞在小鼠体内的侵袭、迁移和转移。有趣的是，我们最近的研究表明，细胞暴露在尼古丁中会激活TBK1，并促进尼古丁介导的细胞增殖。级别 在人类肿瘤样本和暴露于尼古丁的小鼠肿瘤中，活性磷酸化的TBK1都升高。此外，TBK1与E2F1转录因子在物理上相互作用，并有效地将其磷酸化，增强E2F1介导的转录。TBK1还能以E2F1依赖的方式诱导MMP9和14的内源性启动子的表达。基于这些观察，我们推测TBK1是K-RAS和烟碱型乙酰胆碱受体(NAChR)介导的信号转导的重要下游靶点，并通过E2F1调节促进肺癌的进展和转移。基于这一假设，我们认为小分子抑制剂TBK1和E2F1联合应用可有效抑制非小细胞肺癌的生长和转移。我们相信，这些研究具有很高的创新性，将对我们抗击非小细胞肺癌的努力产生重大影响。