Role of succinate dehydrogenase in ovarian cancer metabolism

琥珀酸脱氢酶在卵巢癌代谢中的作用

• 批准号: 10571900
• 负责人: Magdalena Bieniasz
• 金额: $ 37.57万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-05 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571900
• 关键词: Biological Assay; Biological Markers; Biology; Cancer Patient; Cancer cell line; Cell Proliferation; Cells; Chemoresistance; Cisplatin; DNA biosynthesis; Data; Effectiveness; Energy Metabolism; Enzymes; Evaluation; Fumarates; Generations; Genus Hippocampus; Glycolysis; Goals; Growth; Impairment; Malignant Neoplasms; Malignant neoplasm of ovary; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; NADP; Oklahoma; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen Consumption; Paclitaxel; Pathway interactions; Patient Selection; Patients; Pentosephosphate Pathway; Proliferating; Pyruvate; Reactive Oxygen Species; Recurrent Malignant Neoplasm; Regulation; Research; Respiration; Role; Spirometry; Succinate Dehydrogenase; Succinates; System; Technology; Testing; The Cancer Genome Atlas; Tracer; Tumor Biology; Up-Regulation; Warburg Effect; anaerobic glycolysis; cancer cell; cancer recurrence; cancer therapy; chemotherapy; cytotoxicity; improved; in vivo evaluation; innovation; instrument; knock-down; mortality; neoplastic cell; novel; novel therapeutic intervention; nucleic acid biosynthesis; ovarian neoplasm; overexpression; patient derived xenograft model; patient response; precision medicine; programs; protein expression; pyruvate carrier; response; small molecule inhibitor; treatment response; tumor; tumor growth; tumor metabolism

Chemotherapy-resistant ovarian cancer recurs in ~85% of patients and contributes to high rates of cancer-related mortality. The reprograming of cellular metabolism towards anaerobic glycolysis (the Warburg effect) is an important mechanism of chemotherapy resistance. Precision medicine targeting the unique metabolic state of cancer holds great promise to improve the efficacy of ovarian cancer treatment and reduce chemotherapy resistance. From a comprehensive analysis of metabolic pathways in our patient-derived ovarian tumors and The Cancer Genome Atlas (TCGA) data, we discovered that a key mitochondrial enzyme, succinate dehydrogenase (SDHA), is significantly upregulated in 19% of ovarian cancer patients, and is associated with significantly improved patient survival. Our preliminary studies indicate that elevated SDHA increases mitochondrial pyruvate carrier 1 (MPC1) protein expression, which increases pyruvate import to mitochondrial leading to reversal of the Warburg effect and suppression of cell proliferation. In addition, our preliminary data shows that elevated SDHA contributes to imbalance of redox systems, which may sensitize ovarian cancer cells to chemotherapy and/or agents that generate reactive oxygen species (ROS). The overall goal of this study is to determine the mechanism by which elevated SDHA alters ovarian tumor biology to take full advantage of druggable metabolic vulnerabilities such as increased sensitivity to chemotherapy and/or ROS-generating agents to improve patient survival. In Aim 1, we will determine the mechanism by which elevated SDHA reprograms cellular metabolism to regulate ovarian cancer cell proliferation. We will overexpress or knockdown SDHA in ovarian cancer cell lines followed by metabolic and functional characterization of the cells including an evaluation of glycolysis, oxygen consumption and pyruvate transport into mitochondria by Seahorse XF Technology, mass spectrometry and metabolic tracer analyses. We will explore the independent roles of elevated SDHA, SDHA substrates (succinate, fumarate), or MPC1 in reprograming of cellular metabolism and cell proliferation. In Aim 2, we will determine if elevated SDHA, by impairing cellular redox regulation, increases ovarian tumor sensitivity to chemotherapy (cisplatin/paclitaxel) and/or a ROS-generating agent (elesclomol). We will test the effect of SDHA on increasing mitochondrial-dependent respiration and ROS generation by performing respirometry analyses. Finally, we will test in vivo if SDHA-amplified ovarian tumors show better responses to chemotherapy and/or elesclomol using selected patient-derived xenografts (PDXs). The immediate contribution of this project is to explore the novel role of SDHA in changing mitochondrial energy metabolism to improve ovarian cancer patient survival by suppressing of tumor growth and/or increasing the effectiveness of chemotherapy to kill tumor cells. This study is a critical step toward our long-term goal, to develop innovative ways to precisely modulate ovarian cancer-specific metabolism to improve patients’ response to therapy and survival.

抗化疗的卵巢癌在约85％的患者中复发，并导致癌症相关的率很高 死亡。细胞代谢对厌氧糖酵解（沃伯格效应）的重编程是一种 化学疗法抗性的重要机制。精密药物针对独特的代谢状态 癌症具有提高卵巢癌治疗效率并降低化学疗法的巨大希望 反抗。从我们患者衍生的卵巢肿瘤中的代谢途径的全面分析和 癌症基因组地图集（​​TCGA）数据，我们发现关键的线粒体酶是琥珀酸酯 脱氢酶（SDHA）在19％的卵巢癌患者中显着更新，并且与 显着改善了患者的生存率。我们的初步研究表明，SDHA升高增加 线粒体丙酮酸载体1（MPC1）蛋白表达，增加丙酮酸进口到线粒体 导致扭转沃堡效应和细胞增殖的抑制。此外，我们的初步数据 表明SDHA升高会导致氧化还原系统的失衡，这可能会感觉到卵巢癌细胞 对于产生活性氧（ROS）的化学疗法和/或药物。这项研究的总体目标 是为了确定SDHA升高会改变卵巢肿瘤生物学的机制，以充分利用 可吸毒的代谢脆弱性，例如对化学疗法和/或ROSENERED的敏感性提高 改善患者生存的代理。在AIM 1中，我们将确定升高SDHA的机制 重新编程细胞代谢以调节卵巢癌细胞增殖。我们将过表达或敲除 卵巢癌细胞系中的SDHA随后是代谢和功能表征，包括 通过海马XF评估糖酵解，氧气消耗和丙酮酸转运到线粒体 技术，质谱和代谢示踪剂分析。我们将探讨 升高的SDHA，SDHA底物（琥珀酸酯，富马酸盐）或MPC1在重新编程的细胞代谢和 细胞增殖。在AIM 2中，我们将通过损害细胞氧化还原调节来确定是否升高SDHA，增加 卵巢肿瘤对化学疗法（顺铂/紫杉醇）和/或ROS-GENERANET剂（Elesclomol）的敏感性。我们 将测试SDHA对增加线粒体依赖性呼吸和ROS产生的影响 进行呼吸测定分析。最后，如果SDHA扩增的卵巢肿瘤显示更好，我们将在体内测试 使用选定的患者衍生的Xenographictic（PDXS）对化学疗法和/或Elesclomol的反应。这 该项目的直接贡献是探索SDHA在改变线粒体能量中的新作用 代谢来改善卵巢癌患者的生存，通过抑制肿瘤生长和/或增加 化学疗法杀死肿瘤细胞的有效性。这项研究是朝着我们的长期目标迈出的关键一步 开发创新的方法来精确调节卵巢癌特异性代谢以改善患者的反应 治疗和生存。