Role of the mitochondrial citrate carrier SLC25A1(CIC)in cancer progression and therapy

线粒体柠檬酸载体SLC25A1（CIC）在癌症进展和治疗中的作用

• 批准号: 9235268
• 负责人: MARIA L AVANTAGGIATI
• 金额: $ 35.57万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-21 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235268
• 关键词: Adult; Affect; Autophagocytosis; Benzene; Biopsy; Bypass; Cancer cell line; Cells; Cellular Metabolic Process; Chemicals; Citrates; Complement; Data; Disease; Environment; Enzyme Inhibitor Drugs; Exhibits; Fostering; Gluconeogenesis; Glucose; Glycolysis; Goals; Growth; Homeostasis; Lead; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Mediator of activation protein; Metabolic; Mitochondria; Molecular; Mus; NMR Spectroscopy; Nutrient; Nutritional; Oncogenic; Organelles; Outcome; Pathway interactions; Patients; Play; Process; Production; Prognostic Factor; Proteins; Resistance; Role; Stress; Supporting Cell; Testing; Tumor Expansion; Tumor-Derived; Tumorigenicity; Warburg Effect; aerobic glycolysis; base; cancer cell; cancer subtypes; cancer therapy; chemotherapy; citrate carrier; clinically relevant; effective therapy; fasting glucose; glucose metabolism; improved; in vivo; inhibitor/antagonist; insight; lung xenograft; metabolic profile; mimetics; mitochondrial dysfunction; mouse model; neoplastic cell; novel; novel therapeutics; pre-clinical; prevent; prognostic; programs; public health relevance; rapid growth; response; therapeutic target; tricarboxylate; tumor; tumor metabolism; tumor progression; tumorigenesis; tumorigenic

 DESCRIPTION (provided by applicant): Targeting the metabolism of tumor cells is now well recognized as a powerful strategy to develop new therapeutics which could improve treatment options especially of tumor types that are resistant to standard chemo-therapy. Most of previous studies have focused on the precept that the mitochondria are dysfunctional in cancer cells and that tumors depend upon glycolysis for growth (the Warburg effect). This proposal provides a paradigm-concept shift from this view, with our discovery that the mitochondrial citrate transporter SLC25A1 (CIC) is up-regulated in many cancers, is necessary for continuous tumor outgrowth, yet supports proliferation by actually promoting mitochondrial function and by blunting glycolysis. We have also shown that CIC is necessary for the survival response that cancer cells mount in order to adapt to restriction of glucose and to mitochondrial damage. These two forms of stress inevitably ensue in the limiting microenvironment due to the irregularity of the vasculature and pose an important obstacle to the expansion of tumor cells. Thus, our data place CIC activity at the core of the mechanisms by which cancer cells acquire a proliferation advantage in these conditions. Our results specifically show that CIC promotes metabolic adaptation by enacting the switch from glycolysis to gluconeogenesis and by enhancing mitochondrial amount and activity. We have also identified two chemical inhibitors of CIC that display anti-tumor activity as single agents and are non toxic in adult mice. Based on these premises this proposal has three objectives. In Aim 1 we will test the idea, supported by our preliminary data, that CIC maintains the homeostatic control of the tumor mitochondria by inhibiting the rates of mitochondrial degradation and by interfering with the mitochondrial division machinery. We show that through these activities CIC promotes an increase of mitochondrial amount during stress conditions that, in the absence of CIC, would instead lead to mitochondrial depletion, thus depriving tumor cells of their power engine. In Aim 2 we will use NMR spectroscopy and metabolic profiling to confirm our preliminary findings that CIC promotes metabolic plasticity by influencing mitochondrial and cytoplasmic pathways of energy production, thus enacting adaptation to stress. In Aim 3 we will exploit pre-clinical mouse models to study the chemo-therapeutic potential of CIC inhibitor compounds. This will be achieved by employing canonical cancer cell lines as well as patient-derived tumor biopsies expanded as conditionally reprogrammed cells (CRC). The emphasis of these in vivo studies will be on lung cancer based on the important observations that high CIC expression levels predict the poorest prognostic outcome in patients affected by this disease and that CIC promotes the rapid outgrowth of lung cancer cells in vivo. The ultimate goal of these studies is to obtain proof of principle that CIC inhibitors will allow the more effective treatment of well-defined and clinically relevant lung cancer sub-types that are otherwise difficult to target with currently available chemo-therapy.

 描述（由申请人提供）：靶向肿瘤细胞的代谢现在被公认为是开发新疗法的有力策略，其可以改善治疗选择，特别是对标准化疗有抗性的肿瘤类型。以前的大多数研究都集中在癌细胞中线粒体功能失调以及肿瘤依赖糖酵解生长（瓦尔堡效应）的概念上。这一提议提供了从这一观点的范式概念转变，我们发现线粒体柠檬酸盐转运蛋白SLC25A1（CIC）在许多癌症中上调，是连续肿瘤生长所必需的，但通过实际促进线粒体功能和钝化糖酵解来支持增殖。我们还表明，CIC是必要的生存反应，癌细胞安装，以适应限制葡萄糖和线粒体损伤。由于血管系统的不规则性，这两种形式的应力不可避免地发生在有限的微环境中，并对肿瘤细胞的扩张构成重要障碍。因此，我们的数据将CIC活性置于癌细胞在这些条件下获得增殖优势的机制的核心。我们的研究结果特别表明，CIC通过制定从糖酵解到异生的转换和通过增加线粒体的数量和活性来促进代谢适应。我们还鉴定了两种CIC化学抑制剂，其作为单一药剂显示抗肿瘤活性，并且在成年小鼠中无毒。根据这些前提，本建议有三个目标。在目标1中，我们将测试由我们的初步数据支持的想法，即CIC通过抑制线粒体降解速率和干扰线粒体分裂机制来维持肿瘤线粒体的稳态控制。我们表明，通过这些活动，CIC在应激条件下促进线粒体数量的增加，在没有CIC的情况下，反而会导致线粒体耗竭，从而剥夺肿瘤细胞的动力引擎。在目标2中，我们将使用NMR光谱和代谢分析来证实我们的初步发现，即CIC通过影响线粒体和细胞质的能量产生途径来促进代谢可塑性，从而适应压力。在目标3中，我们将利用临床前小鼠模型来研究CIC抑制剂化合物的化学治疗潜力。这将通过采用典型的癌细胞系以及作为条件性重编程细胞（CRC）扩增的患者来源的肿瘤活检来实现。这些体内研究的重点将是肺癌，基于重要的观察结果，即高CIC表达水平预测受这种疾病影响的患者的预后最差，并且CIC促进体内肺癌细胞的快速生长。这些研究的最终目标是获得CIC抑制剂将允许更有效地治疗明确定义和临床相关的肺癌亚型的原则证据，这些肺癌亚型难以用目前可用的化疗靶向。