Vitamin D, Metabolic Flux and Breast Cancer

描述（由申请人提供）：大多数癌细胞依赖于改变的代谢来维持快速增殖。发生在癌细胞中的“代谢开关”与特定的癌基因和肿瘤抑制基因（myc，p53）有关。表达p53的正常细胞具有高GLS 2（磷酸活化的谷氨酸氨酶）活性，其通过TCA循环分流谷氨酸并提供谷胱甘肽（GSH）合成和抗氧化防御。这些数据表明，谷氨酸通量的调节有助于p53的肿瘤抑制作用，并提高了模拟p53对代谢的影响的膳食剂可能有效预防癌症的可能性。通过基因组分析，我们确定了SLC 1A 1（谷氨酸转运蛋白）和GLUL（谷氨酰胺合成酶）作为维生素D调节基因，这表明，像p53一样，维生素D可能通过调节谷氨酸代谢来降低转化风险。假设和目标：我们推测维生素D对SLC 1A 1和GLUL的调节改变了谷氨酸/谷氨酰胺池，并抑制了与肿瘤发生相关的代谢开关。这一假说预测，维生素D维持高细胞内谷氨酸，以增强线粒体呼吸和TCA循环，并促进GSH合成。在目的1中，将评估生理浓度的25-羟基维生素D（25 D）对非转化乳腺细胞中代谢基因表达和谷氨酸/谷氨酰胺代谢的影响与GSH合成和增殖的关系。我们还将进行代谢组学分析，以确定维生素D的反应途径。在目标2中，我们将开发模拟癌症相关代谢紊乱的细胞模型，以测试25 D是否可以预防代谢变化。在目标3中，我们将使用动物模型来确定膳食维生素D是否会改变正常乳腺或“高危”乳腺组织中SLC 1A 1和GLUL的表达/活性，以预防肿瘤。相关性：虽然一些流行病学研究支持维生素D在乳腺癌预防中的作用，但关于具体目标和机制，组织特异性以及维生素D的最佳摄入量以最大限度地提高癌症风险的潜在益处仍然存在问题。医学研究所最近评估了已发表的关于维生素D和癌症的文献，并确定需要进行更多的研究，以制定预防癌症的维生素D摄入指南。在拟议的项目中，我们将研究维生素D状态和代谢之间的关系，在小鼠乳腺癌模型中使用饮食操纵诱导广泛的血清25 D水平代表人类维生素D缺乏，充足和过量。虽然我们的饮食研究将在小鼠中进行，但饮食维生素D和血清25 D之间的保守关系将为外推到人类群体提供起点。

DESCRIPTION (provided by applicant): Most cancer cells rely on altered metabolism to sustain rapid proliferation. The "metabolic switch" that occurs in cancer cells has been linked to specific oncogenes and tumor suppressors (myc, p53). Normal cells expressing p53 have high GLS2 (phosphate-activated glutaminase) activity that shunts glutamate through the TCA cycle and provides for glutathione (GSH) synthesis and antioxidant defense. These data suggest that regulation of glutamate flux contributes to the tumor suppressive actions of p53, and raise the possibility that dietary agents that mimic the effects of p53 on metabolism might be effective in cancer prevention. Through genomic profiling, we identified SLC1A1 (a glutamate transporter) and GLUL (glutamine synthetase) as vitamin D regulated genes suggesting that, like p53, vitamin D might act to reduce risk of transformation by regulation of glutamate metabolism. Hypothesis and Objectives: We hypothesize that regulation of SLC1A1 and GLUL by vitamin D alters glutamate/glutamine pools and suppresses the metabolic switch associated with tumorigenesis. This hypothesis predicts that vitamin D maintains high intracellular glutamate to enhance mitochondrial respiration and the TCA cycle and promote GSH synthesis. In Aim 1, the effects of physiological concentrations of 25- hydroxyvitamin D (25D) on metabolic gene expression and glutamate/glutamine metabolism in non- transformed mammary cells will be assessed in relation to GSH synthesis and proliferation. We will also conduct metabolomics analysis to identify vitamin D responsive pathways. In Aim 2, we will develop cellular models that mimic cancer-associated metabolic disturbances to test whether 25D can prevent changes in metabolism. In Aim 3, we will use animal models to determine whether dietary vitamin D alters SLC1A1 and GLUL expression/activity in normal mammary gland or in "at-risk" mammary tissue in relation to tumor prevention. Relevance: While some epidemiologic studies support a role for vitamin D in breast cancer prevention, questions remain regarding specific targets and mechanisms, tissue specificity, and optimal intakes of vitamin D to maximize potential benefits on cancer risk. The Institute of Medicine recently evaluated published literature on vitamin D and cancer and determined that additional research is needed to establish guidelines for vitamin D intake with respect to cancer prevention. In the proposed project, we will examine the relationship between vitamin D status and metabolism in mouse models of breast cancer using dietary manipulation to induce a wide range of serum 25D levels representative of human vitamin D deficiency, sufficiency and excess. Although our dietary studies will be conducted in mice, the conserved relationship between dietary vitamin D and serum 25D will provide a starting point for extrapolation to human populations.