Research Project
10297376
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.
