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: 10090981
• 负责人: Magdalena Bieniasz
• 金额: $ 34.96万
• 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/10090981
• 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; Patients; Pentosephosphate Pathway; Proliferating; Pyruvate; Reactive Oxygen Species; Regulation; Research; Respiration; Role; Succinate Dehydrogenase; Succinates; System; Technology; Testing; The Cancer Genome Atlas; Tracer; Tumor Biology; Up-Regulation; Warburg Effect; anaerobic glycolysis; base; cancer cell; cancer therapy; chemotherapy; cytotoxicity; improved; in vivo evaluation; innovation; instrument; knock-down; mortality; neoplastic cell; novel; nucleic acid biosynthesis; ovarian neoplasm; overexpression; patient derived xenograft model; patient response; precision medicine; protein expression; pyruvate carrier; response; small molecule inhibitor; treatment strategy; 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.

化疗耐药的卵巢癌在约85%的患者中复发，并导致癌症相关的高发病率。 mortality.细胞代谢向无氧糖酵解的重新编程（瓦尔堡效应）是一种新的代谢途径。 化疗耐药的重要机制。精准医学针对的是 癌症有很大的希望，以提高卵巢癌治疗的疗效，减少化疗 阻力从我们对患者来源的卵巢肿瘤代谢途径的全面分析， 癌症基因组图谱（TCGA）数据，我们发现一个关键的线粒体酶，琥珀酸， 脱氢酶（SDHA）在19%的卵巢癌患者中显著上调，并且与 显著提高患者生存率。我们的初步研究表明，SDHA升高 线粒体丙酮酸载体1（MPC 1）蛋白表达，增加丙酮酸输入线粒体 导致瓦尔堡效应的逆转和细胞增殖的抑制。此外，我们的初步数据显示， 显示升高的SDHA有助于氧化还原系统的失衡，这可能使卵巢癌细胞敏感 涉及化学疗法和/或产生活性氧（ROS）的试剂。本研究的总体目标是 目的是确定SDHA升高改变卵巢肿瘤生物学的机制，以充分利用 药物代谢脆弱性，如对化疗和/或ROS生成的敏感性增加 提高患者生存率。在目标1中，我们将确定SDHA升高的机制， 重新编程细胞代谢以调节卵巢癌细胞增殖。我们将过度表达或击倒 卵巢癌细胞系中的SDHA，随后是细胞的代谢和功能表征，包括 海马XF对糖酵解、氧消耗和丙酮酸转运到线粒体中的评价 技术、质谱和代谢示踪剂分析。我们将探讨的独立作用， SDHA、SDHA底物（琥珀酸盐、富马酸盐）或MPC 1在细胞代谢重编程中升高， 细胞增殖在目标2中，我们将确定是否升高的SDHA，通过损害细胞氧化还原调节，增加 卵巢肿瘤对化疗（顺铂/紫杉醇）和/或ROS生成剂（elesclomol）的敏感性。我们 将测试SDHA对增加呼吸依赖性呼吸和ROS产生的影响， 进行呼吸测定分析。最后，我们将在体内测试SDHA扩增的卵巢肿瘤是否表现出更好的 使用选定的患者来源的异种移植物（PDX）来评估对化疗和/或艾司洛尔的反应。的 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 通过抑制肿瘤生长和/或增加卵巢癌患者的代谢来改善卵巢癌患者的存活率。 化疗杀死肿瘤细胞的有效性。这项研究是实现我们长期目标的关键一步， 开发创新方法，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