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Mechanism of extracellular citrate uptake and metabolism in cancer; specificity and potential use of gluconate in cancer therapy

癌症细胞外柠檬酸摄取和代谢机制；

基本信息

批准号：
411622433
负责人：
Professor Dr. Jerzy Adamski
金额：
--
依托单位：
Klinik und Poliklinik für Chirurgie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2018
资助国家：
德国
起止时间：
2017-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/411622433?language=en
关键词：
Mechanism extracellular citrate uptake metabolism

项目摘要

To metastasize and proliferate, cancer cells need to adjust their metabolism to the increased need for energy and protein synthesis. Warburg effect, the switch from oxidative phosphorylation to anaerobic glycolysis, is considered a hallmark of cancer. Interestingly, citrate as the primary substrate in fatty acid synthesis occupies a central role in cancer cell metabolism, and therefore has been studied extensively. The source of citrate in cancer cells presents a particularly interesting and important question because mitochondria which supply citrate necessary for normal cell metabolism are known to have reduced activity in cancer. Alternatively, glutamine reductive carboxylation has been suggested as the main source of citrate in malignant cells. We have recently discovered that cancer cells unexpectedly take up extracellular citrate and use it to support their metabolism. Plasma membrane citrate transporter (pmCiC) was cloned from cancer cells and determined to be responsible for citrate import. Moreover, our studies indicate that the pmCiC is expressed in human tissues and its expression is mainly restricted to cancer cells, correlating with their stage and metastatic potential. Importantly, we have found gluconate to be an irreversible inhibitor of the pmCiC and show in pilot experiments that treatment of experimental pancreatic cancer with gluconate in vivo results in significantly decreased cancer growth and markedly changes metabolic characteristics of tumor tissues.In the present project we will: (1) study the mechanisms of citrate uptake and metabolism by cancer cells, (2) stably silence pmCiC using CRISPR-Cas9 technique, (3) determine the specificity of gluconate towards pmCiC and test effects of gluconate on cancer versus benign cells, (4) test therapeutic effects of pmCiC inhibition through stable silencing or with gluconate on cancer development in a preclinical in vivo model, (5) more precisely determine pmCiC expression in normal versus cancer cells, and (6) determine pmCiC expression as a marker of tumor progression/stage.The proposed studies will further reveal this novel mechanism supporting cancer cell metabolism that can potentially be exploited therapeutically to treat cancer. Furthermore, determination of citrate transporter expression in human tissues will be useful in establishing its potential as a molecular marker of cancer progression.

为了转移和增殖，癌细胞需要调整其新陈代谢以适应能量和蛋白质合成增加的需求。瓦伯格效应，即从氧化磷酸化到无氧糖酵解的转变，被认为是癌症的标志。有趣的是，柠檬酸盐作为脂肪酸合成的主要底物在癌细胞代谢中发挥着核心作用，因此已被广泛研究。癌细胞中柠檬酸盐的来源提出了一个特别有趣和重要的问题，因为已知提供正常细胞代谢所需柠檬酸盐的线粒体在癌症中活性降低。或者，谷氨酰胺还原羧化被认为是恶性细胞中柠檬酸盐的主要来源。我们最近发现癌细胞意外地吸收细胞外柠檬酸盐并用它来支持它们的新陈代谢。从癌细胞中克隆质膜柠檬酸转运蛋白 (pmCiC)，并确定其负责柠檬酸的输入。此外，我们的研究表明pmCiC在人体组织中表达，其表达主要限于癌细胞，与癌细胞的分期和转移潜力相关。重要的是，我们发现葡萄糖酸盐是 pmCiC 的不可逆抑制剂，并在初步实验中表明，用葡萄糖酸盐体内治疗实验性胰腺癌会显着降低癌症生长并显着改变肿瘤组织的代谢特征。在本项目中，我们将：（1）研究癌细胞摄取柠檬酸盐和代谢的机制，（2）使用葡萄糖酸盐稳定沉默 pmCiC CRISPR-Cas9 技术，(3) 确定葡萄糖酸盐对 pmCiC 的特异性，并测试葡萄糖酸盐对癌症与良性细胞的影响，(4) 在临床前体内模型中测试通过稳定沉默或葡萄糖酸盐抑制 pmCiC 对癌症发展的治疗效果，(5) 更精确地确定正常细胞与癌细胞中的 pmCiC 表达，以及 (6) 确定 pmCiC 表达作为肿瘤标志物进展/阶段。拟议的研究将进一步揭示这种支持癌细胞代谢的新机制，有可能用于治疗癌症。此外，测定人体组织中柠檬酸转运蛋白的表达将有助于确定其作为癌症进展分子标志物的潜力。