Cytochrome C Oxidase in Malignant Gliomas

恶性胶质瘤中的细胞色素 C 氧化酶

• 批准号: 9027806
• 负责人: Corinne E. Griguer
• 金额: $ 30.4万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027806
• 关键词: Accounting; Affect; Affinity; Apoptosis; Apoptotic; Biopsy; Brain Neoplasms; Cancer Etiology; Cell Cycle; Cell Death; Cells; Chromosomes; Complex; Coupled; Cytochromes; DNA; DNA Repair Enzymes; Data; Development; Drug resistance; Electron Transport; Enzymes; Exhibits; Generations; Genes; Genetic; Glioblastoma; Glioma; Goals; Homeostasis; Human; Hypoxia Pathway; Integral Membrane Protein; Intracranial Neoplasms; Kinetics; Lipids; MGMT gene; Malignant Glioma; Mediating; Methylation; Mitochondria; Mitochondrial Proteins; Modality; Molecular; Nuclear; Outcome; Oxidases; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Regulation; Oxidative Stress; Oxygen; Palliative Care; Pathway interactions; Patients; Pharmacotherapy; Production; Prognostic Marker; Progression-Free Survivals; Property; Protein Isoforms; Proteins; Publishing; Radiation therapy; Reactive Oxygen Species; Recurrence; Recurrent tumor; Regimen; Regulation; Research; Resistance; Resistance development; Role; Specimen; Stress; Structure; Survival Rate; Testing; Therapeutic; Tissues; base; cancer cell; cancer therapy; chemotherapy; clinically significant; cytochrome c; cytochrome c oxidase; experience; glucose uptake; inhibitor/antagonist; knowledge base; mitochondrial metabolism; mouse model; mutant; novel; novel marker; novel therapeutics; outcome forecast; overexpression; oxidation; palliative; preconditioning; prognostic tool; protein complex; respiratory; response; standard of care; temozolomide; therapeutic target; therapy outcome; tumor

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common primary intracranial neoplasm and its almost uniform lethality. Temozolomide (TMZ) is the standard of care for the treatment of GBM patients showing small but significant increases in median survival of 4 weeks. However, acquisition of TMZ-chemoresistance is one of the major obstacles to efficient therapy for GBM patients. Despite aggressive treatment approaches, recurrence occurs in 90% of GBM patients. One cause of this poor outcome is development of a drug resistance. The mechanism underlying drug resistance is still not well understood thus challenging the development of more effective strategies and/or novel therapeutics to overcome this resistance. Mitochondria (mt) are at the cross road of energy production and apoptotic pathways. Their role in cancer etiology is significant; however, information regarding mt function and chemoresistance remains poorly defined. The enzyme cytochrome c oxidase (CcO) (EC 1.9.3.1) is a large mt transmembrane protein complex. It is the last enzyme in the respiratory electron transport chain (ETC) that transfers electrons from cytochrome c (Cyt c) to molecular oxygen (O2). Cyt c and O2 are the main substrates of CcO and both are directly involved in the intrinsic mt apoptotic pathway and hypoxia. While most of the studies to date have focus on CcO involvement in mt oxidative phosphorylation, any casual relation between CcO activity, CcO-nuclear-encoded subunits and the development of resistance to apoptosis in GBM is unclear and is the subject of this proposal. Recently, we demonstrated that acquisition of TMZ-resistance correlates with a significant increase of CcO activity in culture glioma cells as well a paired primary-recurrent GBM patient biopsies. The discovery of similar alterations in CcO activity between primary and recurrent human GBM specimens in patients subjected to TMZ-radiotherapy emphasizes the clinical significance of the findings and the primary role of TMZ in mediating these effects. Moreover, pharmacological or genetic inhibition of CcO in TMZ-resistant cells restores TMZ-induced apoptosis. The goal of this proposal is to test the hypothesis that CcO subunit 4 isoform 1 (COX4-1) drives chemoresistance in GBM through changes in 1) CcO assembly/ function and 2) cellular redox homeostasis by achieving three specific aims: We will determine whether: (1) Determine the effects of COX4-1 and 2 isoforms on the assembly/ function of CcO and on resistance to TMZ, (2) Determine the effects of COX4-1 and 2 isoforms on cellular redox status and on resistance to TMZ and 3) Determine the activity of CcO and expression of COX4-1 and 2 isoforms in brain tumor patient biopsies. Upon completion of this research, we expect to have developed a substantial base of knowledge on the role of CcO in the apoptotic response to TMZ. Our long term goal is to apply this information for the development of CcO-based therapies as well as for the development of prognostic markers for chemoresistance and GBM recurrence.

描述（由申请人提供）：多形胶质母细胞瘤（GBM）是最常见的颅内肿瘤及其几乎均匀的致死性。 Temozolomide（TMZ）是治疗GBM患者的护理标准，表现出4周生存期的中位生存期显着增加。但是，获得TMZ-化学疗程是GBM患者有效治疗的主要障碍之一。尽管采用了积极的治疗方法，但90％的GBM患者发生了复发。这种不良结果的原因之一是耐药性的发展。耐药性的基础机制仍未得到充分理解，因此挑战了更有效的策略和/或新型治疗剂的发展，以克服这种抗性。线粒体（MT）位于能源生产和凋亡途径的十字路口。它们在癌症病因中的作用很重要。但是，有关MT功能和化学抗性的信息仍然很差。酶细胞色素C氧化酶（CCO）（EC 1.9.3.1）是大型MT跨膜蛋白复合物。它是呼吸电子传输链（ETC）中的最后一种酶，将电子从细胞色素c（Cyt c）转移到分子氧（O2）。 Cyt C和O2是CCO的主要底物，两者都直接参与了内在的MT凋亡途径和缺氧。尽管迄今为止的大多数研究都集中在CCO参与MT氧化磷酸化中，但CCO活性，CCO-核编码的亚基与GBM中对凋亡的耐药性的发展之间的任何偶然关系尚不清楚，并且是该提案的主题。最近，我们证明了TMZ抗性的获取与培养胶质瘤细胞中CCO活性的显着增加以及成对的原发性GBM患者活检相关。在接受TMZ-Radiotherapy治疗的患者中，初级和经常性人类GBM标本之间CCO活性的类似变化强调了该发现的临床意义以及TMZ在介导这些作用中的主要作用。此外，耐TMZ耐药细胞中CCO的药理或遗传抑制可恢复TMZ诱导的凋亡。该提案的目的是测试以下假说：CCO亚基4同工型1（COX4-1）通过更改通过1）CCO组装/功能和2）实现三个特定目的来使GBM的化学固定能力提高GBM的化学固有率：（我们将确定：（1）确定COX4-1和2 ISOF对CO的效果的影响，我们将通过：（1）确定对COX和2）对CO的效应的影响。 COX4-1和2的同工型在细胞氧化还原状态以及对TMZ的耐药性和3）确定CCO的活性以及在脑肿瘤患者活检中COX4-1和2同工型的表达。这项研究完成后，我们希望已经建立了有关CCO在对TMZ凋亡反应中的作用的大量知识基础。我们的长期目标是将此信息应用于基于CCO的疗法的开发，以及用于化学耐药性和GBM复发的预后标志物的发展。