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

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。这些基因的致癌表达，统称为癌症-睾丸 抗原(CTA)，已有超过25年的文献记载，然而对其贡献的功能知识 这些基因产物在肿瘤发生中的作用仍然很少。我们最近发现其中一个的表达方式 这些CTA，细胞色素C氧化酶亚单位6b2(COX6B2)，在肺腺癌中被激活。COX6B2是 肿瘤体内外生存所必需的基因及其表达与患者生存期缩短的关系 时间到了。我们发现COX6B2在癌细胞中的表达导致复合体IV活性增加 (细胞色素c-氧化酶)和ATP的产生。基于这些发现，我们断言肿瘤细胞采用 来自动物界中最密集的ATP过程之一的代谢机制：精子运动。 为了验证这一假设，我们建议从不同的生物学角度剖析COX6B2的肿瘤特异性功能 结合结构、细胞生物学和整体动物方法的长度标尺。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是如何被激活的及其对生存的影响3)阐述COX6B2对 肿瘤的发生和体内肿瘤的存活。在目标1中，我们使用结构指导的方法来阐明 COX6B2调节细胞色素C氧化酶活性的机制。在目标2中，我们将调查 低氧肿瘤微环境激活COX6B2及COX6B2如何促进低氧生存 在癌症和精子中。在目标3中，我们将使用原位异种移植来确定COX6B2如何表达 影响体内的肿瘤形成、肿瘤生长和氧化磷酸化。这一事件的意义 建议的工作在于确定肿瘤细胞采用的促进氧化的新机制 磷酸化。目前的电子传递链抑制剂由于缺乏治疗指标而受到阻碍 这一过程在健康组织中的广泛必要性。这项研究提出了一种创新的新解决方案 通过呈现在癌细胞中选择性表达的靶点而缺乏特异性。这项工作的成果 将是一个新的治疗切入点，专门针对肿瘤组织的氧化磷酸化。

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.