The sperm specific protein, COX6B2, promotes metabolic reprogramming in lung adenocarcinoma

精子特异性蛋白 COX6B2 促进肺腺癌的代谢重编程

• 批准号: 10683739
• 负责人: Angelique Wright Whitehurst
• 金额: $ 36.76万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683739
• 关键词: Adopted; Adult; Aneuploidy; Animals; Antigens; Attenuated; Behavior; Biological; Cell Death Signaling Process; Cell Survival; Cells; Characteristics; DNA; DNA Damage; Data; Development; Dimensions; Electron Transport; Environment; Female; Gene Expression; Generations; Genes; Glycolysis; Growth; Human; Hypoxia; In Vitro; Individual; Knowledge; Length; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Messenger RNA; Metabolic; Metastatic Neoplasm to the Lung; Mitochondria; Modality; Modeling; Molecular; Normal tissue morphology; Outcome; Ovary; Oxidases; Oxidative Phosphorylation; Oxygen; Patients; Phenotype; Physiology; Placenta; Post-Translational Protein Processing; Process; Production; Proliferating; Protein Isoforms; Proteins; Sampling; Sequence Alignment; Signal Transduction; Specificity; Sperm Motility; Starvation; Structural Models; Structure; Structure of parenchyma of lung; System; Testing; Testis; Therapeutic; Therapeutic Index; Time; Tissues; Tumor Tissue; Work; Xenograft procedure; cancer cell; cancer therapy; cancer/testis antigen; cell motility; complex IV; cytochrome c oxidase; design; gene product; in vivo; inhibitor; innovation; mRNA Expression; neoplastic cell; novel; novel therapeutics; preservation; programs; protein expression; reproductive tract; selective expression; sperm cell; success; therapeutic target; tumor; tumor growth; tumor hypoxia; tumor microenvironment; tumor xenograft; tumorigenesis; tumorigenic

Project Abstract Tumors frequently re-activate genes whose expression is otherwise restricted to gametogenic tissues including the ovary, placenta and testes. Tumorigenic expression of these genes, known collectively as cancer-testes antigens (CTAs), has been documented for over 25 years, however functional knowledge of the contribution of these gene products to tumorigenesis remains scant. We have recently discovered that expression of one of these CTAs, Cytochrome C Oxidase subunit 6B2 (COX6B2), is activated in lung adenocarcinoma. COX6B2 is essential for tumor survival in vitro and in vivo and its expression correlates with shortened patient survival time. We have found that expression of COX6B2 in cancer cells leads to an increase in activity of Complex IV (cytochrome c-oxidase) and ATP production. Based on these findings, we assert that tumor cells adopt metabolic mechanisms from one of the most ATP-intensive processes in the animal kingdom: sperm motility. To test this hypothesis, we propose to dissect the tumor-specific function of COX6B2 at multiple biological length scales incorporating structural, cell biological and whole animal approaches. Our specific aims are to 1) dissect the molecular mechanism by which COX6B2 enhances Cytochrome C oxidase activity, 2) determine how COX6B2 is activated and its consequences on survival 3) elaborate the contribution of COX6B2 to tumorigenesis and tumor survival in vivo. In Aim 1, we use a structure-guided approach to elucidate the mechanism by which COX6B2 modulates Cytochrome c oxidase activity. In Aim 2, we will investigate how the low oxygen tumor microenvironment activates COX6B2 and how COX6B2 promotes survival in hypoxia both in cancer and in sperm. In Aim 3, we will use an orthotopic xenograft to determine how COX6B2 expression influences tumorigenesis, tumor growth, and oxidative phosphorylation in vivo. The significance of the proposed work lies in the identification of novel mechanisms that tumor cells adopt to promote oxidative phosphorylation. Current electron transport chain inhibitors are hampered by a lack of therapeutic index due to the broad necessity of this process in healthy tissues. This study proposes an innovative new solution to this lack of specificity by presenting a target that is selectively expressed in cancer cells. The outcome of this work will be a novel therapeutic entry point for targeting oxidative phosphorylation exclusively in tumor tissues.

项目摘要 肿瘤经常重新激活基因，这些基因的表达否则仅限于配子发生组织，包括 卵巢胎盘和睾丸这些基因的致瘤性表达统称为睾丸癌 抗原（CTA），已经记录了超过25年，然而，功能知识的贡献， 这些基因产物对肿瘤发生的作用仍然很少。我们最近发现， 这些CTA，细胞色素C氧化酶亚基6B2（COX 6B2），在肺腺癌中被激活。COX6B2是 在体外和体内对肿瘤存活是必需的，并且其表达与缩短的患者存活相关 时间我们已经发现，COX6B2在癌细胞中的表达导致复合物IV的活性增加 （细胞色素c氧化酶）和ATP产生。基于这些发现，我们断言肿瘤细胞采用 在动物王国中，ATP最密集的过程之一的代谢机制：精子运动。 为了验证这一假设，我们建议从多个生物学角度剖析COX6B2的肿瘤特异性功能。 长度尺度结合结构，细胞生物学和整个动物的方法。我们的具体目标是：（1） 剖析COX6B2增强细胞色素C氧化酶活性的分子机制，2）确定 COX6B2如何被激活及其对生存的影响3）阐述COX6B2对 肿瘤发生和体内肿瘤存活。在目标1中，我们使用结构引导的方法来阐明 COX6B2调节细胞色素c氧化酶活性的机制。在目标2中，我们将研究 低氧肿瘤微环境激活COX6B2，以及COX6B2如何促进低氧中的存活， 在癌症和精子中。在目标3中，我们将使用原位异种移植物来确定COX6B2表达 影响肿瘤发生、肿瘤生长和体内氧化磷酸化。的意义 建议的工作在于确定肿瘤细胞促进氧化的新机制， 磷酸化目前的电子传递链抑制剂由于缺乏治疗指数而受到阻碍， 这一过程在健康组织中的广泛必要性。这项研究提出了一个创新的解决方案， 通过呈递在癌细胞中选择性表达的靶标而缺乏特异性。这项工作的成果 将是一种新的治疗切入点，专门针对肿瘤组织中的氧化磷酸化。