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: 10339352
• 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/10339352
• 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 response; 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 死亡。细胞代谢向无氧糖酵解（瓦尔堡效应）的重新编程是一种 化疗耐药的重要机制。针对独特代谢状态的精准医学 癌症有望提高卵巢癌治疗效果并减少化疗 反抗。通过对患者来源的卵巢肿瘤代谢途径的全面分析， 在癌症基因组图谱（TCGA）数据中，我们发现一种关键的线粒体酶，琥珀酸 脱氢酶 (SDHA) 在 19% 的卵巢癌患者中显着上调，并且与 显着提高了患者的生存率。我们的初步研究表明，SDHA 升高会增加 线粒体丙酮酸载体 1 (MPC1) 蛋白表达，增加丙酮酸向线粒体的输入 导致瓦伯格效应的逆转和细胞增殖的抑制。另外，我们的初步数据 表明 SDHA 升高会导致氧化还原系统失衡，这可能会使卵巢癌细胞变得敏感 化疗和/或产生活性氧 (ROS) 的药物。本研究的总体目标 目的是确定升高的 SDHA 改变卵巢肿瘤生物学的机制，以充分利用 可药物代谢的脆弱性，例如对化疗和/或 ROS 生成的敏感性增加 提高患者生存率的药物。在目标 1 中，我们将确定 SDHA 升高的机制 重新编程细胞代谢来调节卵巢癌细胞增殖。我们会过度表达或敲低 卵巢癌细胞系中的 SDHA，随后对细胞进行代谢和功能表征，包括 通过 Seahorse XF 评估糖酵解、耗氧量和丙酮酸转运至线粒体 技术、质谱分析和代谢示踪分析。我们将探讨独立角色 细胞代谢重编程中 SDHA、SDHA 底物（琥珀酸、富马酸）或 MPC1 升高 细胞增殖。在目标 2 中，我们将确定 SDHA 升高是否会通过损害细胞氧化还原调节来增加 卵巢肿瘤对化疗（顺铂/紫杉醇）和/或 ROS 生成剂（elesclomol）敏感。我们 将测试 SDHA 对增加线粒体依赖性呼吸和 ROS 生成的影响 进行呼吸测量分析。最后，我们将在体内测试 SDHA 扩增的卵巢肿瘤是否表现更好 使用选定的患者来源的异种移植物（PDX）对化疗和/或艾司洛莫的反应。这 该项目的直接贡献是探索 SDHA 在改变线粒体能量方面的新作用 通过抑制肿瘤生长和/或增加卵巢癌患者的新陈代谢来提高卵巢癌患者的生存率 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。