MKP-1 Effects on HIF-1alpha and Glycolytic Metabolism in Glioblastoma multiforme

MKP-1 对多形性胶质母细胞瘤中 HIF-1α 和糖酵解代谢的影响

• 批准号: 8693609
• 负责人: Bradley N. Mills
• 金额: $ 4.27万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693609
• 关键词: Acidosis; Apoptosis; Apoptotic; Architecture; Bioenergetics; Brain; Cell Line; Cell Survival; Cells; Cessation of life; Clinical; DUSP1 gene; Defect; Disease; Functional disorder; Gene Expression Profile; Gene Silencing; Gene Targeting; Genetic; Genetic Transcription; Glioblastoma; Glioma; Growth; HIF1A gene; Homeostasis; Hypoxia; Lactate Transporter; Link; Malignant - descriptor; Malignant Neoplasms; Measures; Messenger RNA; Metabolic; Metabolism; Mitogen-Activated Protein Kinases; Mono-S; Outcome Measure; Oxidative Phosphorylation; Oxygen; Pathway interactions; Pattern; Phenotype; Phosphoric Monoester Hydrolases; Play; Prognostic Marker; Proto-Oncogenes; Recurrence; Regulation; Resected; Resistance; Respiration; Role; Sampling; Signal Pathway; Signal Transduction; Simulate; Solid Neoplasm; Somatic Mutation; Stress; System; TP53 gene; Testing; Therapeutic; Transcriptional Activation; Tumor Markers; Tumor Suppressor Genes; Tumor Suppressor Proteins; U251; Warburg Effect; Western Blotting; carboxylate; cell growth; clinically relevant; hypoxia inducible factor 1; neoplastic cell; new therapeutic target; novel; public health relevance; therapeutic target; transcription factor; tumor; tumor microenvironment; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Two cardinal features of the tumor cell phenotype are a bioenergetic shift toward glycolytic respiration and apoptotic resistance under high stress conditions. A key regulatory node common to each of these pathways is the hypoxia inducible factor-1¿ (HIF-1¿). Regional hypoxia within the microenvironment of glioblastoma multiforme (GBM) and related somatic mutations converge to stimulate HIF-1¿ activity further enhancing tumor progression. In both immortalized GBM lines and primary resected tumor lysates we find that reduced expression of the MAP kinase phosphatase (MKP-1) correlates with the induction of the HIF-1¿ target mono- carboxylate transporter 4 (MCT4), a lactate transporter critical to homeostasis of glycolytic tumors. By genetically manipulating levels of p53 and MKP-1 in the U87 and U251 tumor lines, we seek to establish a role for MKP-1 and MCT4 in GBM. The effects of MKP-1 on glycolytic metabolism will be assessed using transcriptional analyses to identify effects on HIF-1¿ targets involved in metabolism and survival. Consequently, metabolite analyses will establish the functional role of this signaling pathway. We then establish the relevance of this pathway through the combined Western and immunohistochemical analysis of MKP-1 and MCT4 in clinical GBM samples. In aggregate these studies seek to implicate MKP-1 and MCT4 as clinically relevant markers tumor grade, and to investigate their potential role therapeutic targets for this devastating disease.

描述（由申请人提供）：肿瘤细胞表型的两个主要特征是在高应激条件下生物能量向糖酵解呼吸和凋亡抗性的转变。这些途径中的每一个共同的关键调节节点是缺氧诱导因子-1（HIF-1）。多形性胶质母细胞瘤（GBM）微环境内的局部缺氧和相关的体细胞突变会刺激HIF-1活性，进一步促进肿瘤进展。在永生化GBM系和原发性切除肿瘤裂解物中，我们发现MAP激酶磷酸酶（MKP-1）的表达减少与HIF-1靶单羧酸转运蛋白4（MCT 4）的诱导相关，MCT 4是一种对糖酵解肿瘤的稳态至关重要的乳酸转运蛋白。通过遗传操纵U87和U251肿瘤系中p53和MKP-1的水平，我们试图建立MKP-1和MCT 4在GBM中的作用。将使用转录分析评估MKP-1对糖酵解代谢的影响，以确定对参与代谢和存活的HIF-1？靶标的影响。 因此，代谢物分析将确定该信号通路的功能作用。然后，我们通过对临床GBM样本中MKP-1和MCT 4的联合Western和免疫组织化学分析，建立了该途径的相关性。 总的来说，这些研究试图将MKP-1和MCT 4作为临床相关的肿瘤分级标志物，并研究它们在这种毁灭性疾病中的潜在作用和治疗靶点。