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 细胞虽然许多研究都集中在确定参与增加葡萄糖摄取的途径， 由于肿瘤细胞的代谢，许多癌症（特别是急性白血病）不依赖于葡萄糖，而是依赖于葡萄糖。 更喜欢代谢脂肪来支持他们的生存和成长。尽管这种表型普遍存在， 在癌症中调节脂肪酸氧化（FAO）的分子机制在很大程度上仍然未知。作为途径 驾驶燃料成瘾可能为个性化治疗提供新的治疗靶点或生物标志物， 迫切需要确定调节对脂质依赖性的途径。我们发现了一种新的营养素- 通过脯氨酰的一个很少研究的成员控制癌症中脂肪氧化的依赖性信号通路 羟化酶结构域蛋白家族，PHD 3。PHD是α-酮戊二酸依赖性双加氧酶家族， 羟基化底物脯氨酸残基并与癌症中燃料转换有关。我们发现PHD 3 通过羟化乙酰辅酶A羧化酶（ACC 2）调节脂肪酸代谢，ACC 2是线粒体膜电位的调节因子。 粮农组织。响应于营养丰富，PHD 3激活ACC 2以抑制脂肪酸的分解。我们 该提案将检验以下假设，即具有低PHD 3的肿瘤将具有过度的脂肪酸氧化， ACC 2活性失调，PHD 3水平可能提供一种新的代谢生物标志物来识别肿瘤 容易受到针对脂肪代谢的治疗。这项建议将研究机制，其中PHD 3- 介导的羟基化导致ACC 2同种型的特异性活化（Aim 1）。我们亦会研究 生理刺激PHD 3在高营养条件下，并检查其协调与AMPK 信号传导，其通过磷酸化抑制ACC（Aim 2）。最后，我们将研究 PHD 3活性、ACC 2羟基化和FAO在AML存活和生长中的作用 低PHD 3的肿瘤对脂肪氧化抑制剂的过度表达和脆弱性（Aim 3）。我们的总体 我们的目标是阐明PHD 3信号传导的要素，并利用这些发现来开发治疗药物。 治疗依赖于脂肪氧化的肿瘤的策略。