Extracellular Citrate and Cancer Metabolism-Response.
Extracellular Citrate and Cancer Metabolism-Response.
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细胞外柠檬酸盐和癌症代谢反应
DOI：
10.1158/0008-5472.can-18-1899
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发表时间：
2018
期刊：
影响因子：
11.2
通讯作者：
Geissler EK
中科院分区：
文献类型：
--
作者：
Mycielska ME;Geissler EK
针对我们最近的文章显示癌细胞通过线粒体柠檬酸盐转运蛋白的质膜特异性变体（pmCiC）摄取细胞外柠檬酸盐，并且通过阻断pmCiC活性剥夺癌细胞的细胞外柠檬酸盐导致肿瘤生长减少（1），Icard和同事（2）提出了一个有趣的观点，即非常高的浓度（50倍生理水平）的细胞外柠檬酸盐导致癌细胞超载，这也阻止了癌症的生长。虽然这些方法似乎相互矛盾，但它们实际上是基于癌细胞特异性输入细胞外柠檬酸盐的相同能力（1）。”低”和”高”柠檬酸盐摄取方法都有意义，因为低摄取限制了关键癌细胞代谢过程（如脂肪酸合成）的柠檬酸盐可用性（1），而高细胞内柠檬酸盐水平抑制糖酵解并干扰其他细胞功能，这对癌细胞也很重要（2）。因此，干扰细胞内柠檬酸水平的任何一个方向都可能对癌细胞产生不利影响，问题是如何治疗性地操纵细胞外柠檬酸摄取。简单地以治疗性降低或增加血液中的柠檬酸盐水平为目标可能会通过扰乱二价离子螯合作用（3）或通过影响专门的健康细胞（如肝细胞和神经元）在体内产生一些不必要的副作用，这些细胞也依赖于细胞外柠檬酸盐，但通过完全不同的柠檬酸盐转运蛋白家族（4，5）。重要的是，我们认为在这方面特异性攻击癌细胞的一种有希望的方法是通过降低（1）或增强其功能来靶向pmCiC。我们已经发现葡萄糖酸盐阻断pmCiC，但最终可能会发现所谓的治疗性”开放剂”导致柠檬酸盐摄取过量。靶向pmCiC的优点是其表达主要限于人类癌细胞，并且在转移灶和侵袭部位特别高（1）。因此，我们同意Icard及其同事（2）的观点，即减少或增加癌细胞对细胞外柠檬酸盐的摄取是癌症治疗的一个有趣选择。此外，我们认为，治疗靶向pmCiC是一个科学合理的选择，以实现肿瘤特异性的有效性。
In response to our recent article showing that cancer cells take up extracellular citrate through the plasma membrane-specific variant (pmCiC) of the mitochondrial citrate transporter and that depriving cancer cells of extracellular citrate by blocking pmCiC activity results in a decreased tumor growth (1), Icard and colleagues (2) have raised the interesting point that very high concentrations (50x physiologic levels) of extracellular citrate lead to cancer cell overloading, which also deters cancer growth. Although these approaches seem contradictory, they are actually based on the same ability of cancer cells to specifically import extracellular citrate (1). Both the" low" and" high" citrate uptake approaches do make sense, because low uptake limits citrate availability for critical cancer cell metabolic processes such as fatty acid synthesis (1), and high intracellular citrate levels inhibit glycolysis and disturb other cellular functions, which are also important for cancer cells (2). Therefore, disturbing intracellular citrate levels in either direction can have detrimental effects on cancer cells.The question is then how to therapeutically manipulate extracellular citrate uptake. Simply aiming to therapeutically decrease or increase citrate levels in blood could result in some unwanted side effectsin vivo by upsetting divalent ion chelation (3), or by affecting specialized healthy cells such as hepatocytes and neurons, which also depend on extracellular citrate, but via completely different families of citrate transporters (4, 5). Importantly, we suggest that a promising way to specifically attack cancer cells in this respect is to target the pmCiC by either decreasing (1) or enhancing its function. We have found that gluconate blocks the pmCiC, but so-called therapeutic" openers" may eventually be found that cause excessive citrate uptake. The advantage of targeting the pmCiC is that its expression is mainly restricted to cancer cells in humans, and is particularly high in metastases and sites of invasion (1). Therefore, we agree with Icard and colleagues (2) that either decreasing or increasing extracellular citrate uptake by cancer cells is an interesting option for cancer therapy. In addition, we suggest that therapeutically targeting the pmCiC is a scientifically sound option for achieving tumor-specific effectiveness.
DOI：
10.1152/ajpgi.00371.2006
发表时间：
2007-01-01
影响因子：
4.5
作者：
Gopal, Elangovan;Miyauchi, Seiji;Ganapathy, Vadivel
通讯作者：
Ganapathy, Vadivel
摘要 5176：无细胞恶性腹水促进胃腺癌腹膜转移
影响因子：
--
作者：
Chantelle A. Janeiro;Vivian Stavrakos;Malak Alzahrani;R. Rayes;B. Giannias;N. Bertos;V. Sangwan;J. Cools;J. Spicer;L. Ferri
通讯作者：
L. Ferri
细胞外柠檬酸盐和癌症代谢-快报。
影响因子：
11.2
作者：
P. Icard;L. Fournel;M. Alifano;H. Lincet
通讯作者：
H. Lincet