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。这些基因的致瘤表达，统称为癌症睾丸 抗原 (CTA) 的记录已超过 25 年，但关于其贡献的功能性知识 这些与肿瘤发生有关的基因产物仍然很少。我们最近发现其中之一的表达 这些 CTA（细胞色素 C 氧化酶亚基 6B2 (COX6B2)）在肺腺癌中被激活。 COX6B2 是 对于体外和体内肿瘤生存至关重要，其表达与患者生存期缩短相关 时间。我们发现癌细胞中 COX6B2 的表达导致复合物 IV 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 动物界中 ATP 最密集的过程之一的代谢机制：精子活力。 为了检验这一假设，我们建议从多个生物学角度剖析 COX6B2 的肿瘤特异性功能。 长度尺度结合了结构、细胞生物学和整体动物方法。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 对生存的贡献 体内肿瘤发生和肿瘤存活。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，我们将研究如何 低氧肿瘤微环境激活 COX6B2 以及 COX6B2 如何促进缺氧生存 在癌症和精子中。在目标 3 中，我们将使用原位异种移植物来确定 COX6B2 表达如何 影响体内肿瘤发生、肿瘤生长和氧化磷酸化。的意义 拟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因缺乏治疗指数而受到阻碍 健康组织中这一过程的广泛必要性。这项研究为此提出了一种创新的解决方案 通过呈现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 将成为专门针对肿瘤组织中氧化磷酸化的新治疗切入点。

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.