Molecular mechanisms of Nutrient sensing in cancer

项目总结 代谢重编程是癌症的一个标志，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葡萄糖摄取增加和 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 喜欢代谢脂肪以支持它们的生存和生长。尽管这种表型很普遍， 调节癌症中脂肪酸氧化(FAO)的分子机制在很大程度上仍不清楚。作为路径 驱动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，有一种 迫切需要确定调节对脂质依赖的途径。我们发现了一种新的营养物质-- 依赖的信号通路通过一个鲜有研究的脯氨酸基成员控制癌症中的脂肪氧化 羟基酶结构域蛋白家族，PHD3。PHD是依赖于α-酮戊二酸的双加氧酶家族， 羟基化底物脯氨酸残基，并已被认为与癌症的燃料转换有关。我们发现PHD3 通过羟化线粒体调节因子乙酰辅酶A羧基酶(ACC2)来调节脂肪酸代谢 粮农组织。作为对营养丰富的反应，PHD3激活ACC2以抑制脂肪酸的分解代谢。我们的 该提案将检验这样的假设，即PHD3低的肿瘤将有过度的脂肪酸氧化，这是由于 ACC2活性的解除调节，PHD3水平可能提供一个新的代谢生物标记物来识别肿瘤 容易受到针对脂肪分解代谢的治疗的影响。这项建议将研究PHD3通过的机制- 介导的羟化导致ACC2亚型的特异性激活(目标1)。我们还将研究 高营养条件下PHD3的生理刺激及其与AMPK的协同作用 信号转导，通过磷酸化抑制ACC(目标2)。最后，我们将研究 PHD3活性、ACC2羟化和FAO在AML生存和生长中的作用 低PHD3肿瘤的过度表达和对脂肪氧化抑制剂的易感性(目标3)。我们最重要的是 目标是阐明PHD3信号的要素，并利用这些发现开发治疗 治疗依赖脂肪氧化的肿瘤的策略。

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.