Molecular mechanisms of Nutrient sensing in cancer

癌症营养感应的分子机制

• 批准号: 9494546
• 负责人: MARCIA HAIGIS
• 金额: $ 37.42万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9494546
• 关键词: Acetyl-CoA Carboxylase; Acute Myelocytic Leukemia; Acute leukemia; Biochemical; Biological Markers; Catabolism; Cell Line; Cell model; Cells; Cellular Assay; Cues; Data; Dependence; Dioxygenases; Elements; Enzyme Activation; Enzymes; Family; Fasting; Fatty Acids; Fatty acid glycerol esters; Glucose; Goals; Growth; Homeostasis; Human; Hydroxylation; Isoenzymes; Knowledge; Link; Lipids; Malignant Neoplasms; Measures; Mediating; Metabolic; Mitochondria; Modification; Molecular; Nutrient; Pathway interactions; Pharmacology; Phenotype; Phosphorylation; Physiological; Procollagen-Proline Dioxygenase; Proline; Protein Family; Protein Isoforms; Publishing; Regulation; Research; Role; Signal Pathway; Signal Transduction; Stimulus; Tertiary Protein Structure; Testing; Therapeutic; Tissues; Tumor Markers; Work; addiction; alpha ketoglutarate; cancer cell; cancer therapy; detection of nutrient; fatty acid metabolism; fatty acid oxidation; glucose metabolism; glucose uptake; improved; in vivo; inhibitor/antagonist; innovation; insight; leukemia; lipid metabolism; member; mouse model; neoplastic cell; new therapeutic target; overexpression; oxidation; personalized medicine; response; targeted treatment; therapeutic biomarker; tumor; tumor metabolism

PROJECT SUMMARY Metabolic reprogramming is a hallmark of cancer that supports the rapid proliferation and survival of tumor cells. While many studies have focused on identifying pathways involved in increased glucose uptake and metabolism by tumor cells, many cancers (particularly acute leukemias) do not depend on glucose and instead prefer to metabolize fats to support their survival and growth. Despite the pervasiveness of this phenotype, molecular mechanisms that regulate fatty acid oxidation (FAO) in cancer remain largely unknown. As pathways that drive fuel addiction may provide new therapeutic targets or biomarkers for personalized therapy, there is a critical need to identify pathways that regulate dependency on lipids. We have discovered a new nutrient- dependent signaling pathway that controls fat oxidation in cancers via a little studied member of the prolyl hydroxylase domain protein family, PHD3. PHDs are a family of α-ketoglutarate dependent dioxygenases that hydroxylate substrate proline residues and have been linked to fuel switching in cancer. We find that PHD3 regulates fatty acid metabolism by hydroxylating acetyl-CoA carboxylase (ACC2), a regulator of mitochondrial FAO. In response to nutrient abundance, PHD3 activates ACC2 to inhibit catabolism of fatty acids. Our proposal will test the hypothesis that tumors with low PHD3 will have excessive fatty acid oxidation due to deregulation of ACC2 activity, and that PHD3 levels may provide a new metabolic biomarker to identify tumors vulnerable to therapies that target fat catabolism. This proposal will examine the mechanism by which PHD3- mediated hydroxylation results in the specific activation of the ACC2 isoform (Aim 1). We will also examine the physiological stimulation of PHD3 under high nutrient conditions, and examine its coordination with AMPK signaling, which represses ACC by phosphorylation (Aim 2). Finally, we will examine the consequences of PHD3 activity, ACC2 hydroxylation, and FAO in AML survival and growth by examining the effects of PHD3 overexpression and vulnerability of tumors with low PHD3 to fat oxidation inhibitors (Aim 3). Our overarching goal is to elucidate the elements of PHD3 signaling and to leverage these findings to develop therapeutic strategies to treat tumors dependent on fat oxidation.

项目摘要 代谢重编程是癌症的标志，支持肿瘤的快速增殖和存活 细胞。尽管许多研究都集中在识别葡萄糖摄取增加的途径和 肿瘤细胞的代谢，许多癌症（尤其是急性白血病）不依赖葡萄糖，而是 宁愿代谢脂肪以支持其生存和生长。尽管这种表型普遍存在，但 癌症中调节脂肪酸氧化（FAO）的分子机制仍然在很大程度上未知。作为路径 驱动燃料成瘾可能会为个性化治疗提供新的治疗靶标或生物标志物 识别调节脂质依赖性的途径的临界需求。我们发现了一种新的营养素 - 依赖信号通路，通过prolyl的一个小研究成员控制癌症中的脂肪氧化 羟化酶结构蛋白家族，PHD3。 PHD是一个α-酮戊二酸酯家族，依赖于双氧酶 羟基底物脯氨酸恢复，并与癌症的燃料转换有关。我们发现PHD3 通过羟基乙酰辅酶A羧化酶（ACC2）调节脂肪酸代谢，线粒体的调节剂 刑事。为了响应营养丰度，PHD3激活ACC2以抑制脂肪酸的分解代谢。我们的 提案将检验以下假设：由于 放松ACC2活性的管制，并且PHD3水平可能会提供一种新的代谢生物标志物来鉴定肿瘤 容易受到靶向脂肪分解代谢的疗法。该提案将研究phd3-的机制 介导的羟基化导致ACC2同工型的特异性激活（AIM 1）。我们还将检查 在高营养条件下对PHD3的生理模拟，并检查其与AMPK的协调 信号传导，通过磷酸化反映ACC（AIM 2）。最后，我们将研究 通过检查PHD3的影响，PHD3活性，ACC2羟基化和粮农 PHD3低对脂肪氧化抑制剂的肿瘤的过表达和脆弱性（AIM 3）。我们的总体 目标是阐明PHD3信号的元素，并利用这些发现来开发治疗 依赖于脂肪氧化的肿瘤的策略。