Investigating Novel Functions for NIK/MAP3K14 in High-Grade Glioma

研究 NIK/MAP3K14 在高级别胶质瘤中的新功能

基本信息

批准号：
10402385
负责人：
RAQUEL SITCHERAN
金额：
$ 32.48万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402385
关键词：
Attenuated Bioenergetics Cell Respiration Cell Survival Cells Cellular Stress Cellular Structures Data Development Energy Metabolism Environment Equilibrium Gene Expression Glioblastoma Glioma Glucose Glycolysis Goals Growth Homeostasis Human IKK alpha In Vitro Infiltrative Growth Knock-out Laboratories MAP3K14 gene Malignant Neoplasms Metabolic Metabolic Pathway Metabolic dysfunction Metabolic stress Metabolism Mitochondria Molecular NF-kappa B Nuclear Nutrient Oncogenic Oxidative Phosphorylation Oxygen Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Phosphotransferases Play Production Prognosis Recurrence Regulation Regulatory Pathway Research Resistance Role Signal Pathway Signal Transduction Starvation Testing Therapeutic base biological adaptation to stress brain tissue cancer cell cancer invasiveness cell motility design detection of nutrient expectation experimental study glucose metabolism improved in vivo inhibitor insight migration mitochondrial dysfunction mitochondrial metabolism neoplastic cell novel novel therapeutic intervention nutrient deprivation response sensor therapy resistant trafficking tumor tumor growth tumor metabolism tumor microenvironment tumor progression tumorigenic

项目摘要

PROJECT SUMMARY Cancer cells are able to adapt to grow uncontrollably and invasively in environments with limited availability of nutrients — most notably, glucose and oxygen. Indeed, the aggressive migration and invasion of high- grade gliomas, including glioblastoma multiforme (GBM), into healthy brain tissue are major factors contributing to the therapy resistance and poor prognosis of this malignancy. While many cancer cells preferentially utilize glycolysis to support growth, GBM cells have been shown to rely on both glycolysis and mitochondrial metabolism for glucose energy utilization. Mitochondrial dynamics, or the balance between mitochondrial fission and fusion, is a central mechanism for bioenergetic adaptations to cellular stresses such as nutrient deprvation. Therefore, targeting de-regulated mitochondrial function is a highly attractive therapeutic strategy for GBM. Recent findings have established key roles for NF-κB-inducing kinase (NIK/MAP3K14) in regulating mitochondrial dynamics and subcellular trafficking to promote the invasiveness and pathogenesis of GBM cells. Moreover, preliminary data demonstrate that mitochondrial NIK enhances the resistance of GBM cells to nutrient/glucose starvation through regulation of mitochondrial metabolism. Moreover, the mitochondrial actions of NIK are independent of its regulation of NF-κB activity. However, the molecular mechanisms by which NIK coordinates regulation of mitochondrial function and metabolic reprogramming in GBM cells are currently not known. This proposal tests the hypothesis that NIK is induced by, and is an important regulator of, mitochondrial dynamics, cancer cell metabolism and infiltrative growth in response to nutrient deprivation. The goals of the proposal are to functionally define NIK-dependent regulatory networks and metabolic pathways that regulate cancer cell mitochondrial functions and test the whether NIK inhibition will sensitize GBM cells to nutrient starvation and attenuate tumor cell survival and pathogenesis. This proposal is anticipated to have an important positive impact because understanding the molecular basis of NIK mitochondrial functions is likely to generate strong justification for the development of novel, mechanism-based therapies for GBM that target mitochondrial dysfunction, invasion, and de-regulated metabolism through NIK inhibition with the ultimate goal of improving patient survival. !

项目摘要癌细胞能够在有限的环境中无法控制地和侵入性地生长营养 - 最值得注意的是葡萄糖和氧气。确实，侵略性迁移和入侵高级别的神经胶质瘤，包括多形胶质母细胞瘤（GBM），进入健康的脑组织是主要因素促进这种恶性肿瘤的耐药性和预后不良。而许多癌细胞优先利用糖酵解来支持生长，GBM细胞已显示出依赖于糖酵解和线粒体代谢用于葡萄糖能利用。线粒体动力或之间的平衡线粒体裂变和融合是生物能适应细胞应激的中心机制例如营养剥夺。因此，靶向脱节的线粒体功能是一种极具吸引力的 GBM的治疗策略。最近的发现已经确立了NF-κB诱导激酶的关键作用（NIK/MAP3K14）在控制线粒体动力学和亚细胞运输方面以促进 GBM细胞的侵入性和发病机理。此外，初步数据证明了线粒体 NIK通过调节线粒体增强了GBM细胞对营养/葡萄糖饥饿的耐药性代谢。此外，NIK的线粒体作用与其对NF-κB活性的调节无关。但是，NIK坐在线粒体功能和 GBM细胞中的代谢重编程目前尚不清楚。该提案检验了尼克的假设是由线粒体动力学，癌细胞代谢和侵入营养剥夺的渗透生长。该提案的目标是在功能上定义依赖NIK的调节网络和代谢途径，可调节癌细胞线粒体功能并测试NIK抑制是否会感知GBM细胞对营养饥饿并减弱肿瘤细胞的存活和发病机理。预计该建议将产生重要的积极影响因为了解NIK线粒体功能的分子基础可能会产生强大开发针对线粒体的GBM的新型，基于机制的疗法的理由通过NIK抑制，功能障碍，侵袭和脱离调节的新陈代谢，最终目标是改善患者的生存。呢

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transcriptional induction of NF-κB-inducing kinase by E2F4/5 facilitates collective invasion of GBM cells.

DOI：
10.1038/s41598-023-38996-9
发表时间：
2023-08-11
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Pflug, Kathryn M.;Lee, Dong W.;McFadden, Kassandra;Herrera, Linda;Sitcheran, Raquel
通讯作者：
Sitcheran, Raquel

Targeting NF-κB-Inducing Kinase (NIK) in Immunity, Inflammation, and Cancer.