柠檬酸在癌症中的双重角色。
The dual role of citrate in cancer.
发表日期：2023 Sep 15
作者：
Philippe Icard, Luca Simula, Grit Zahn, Marco Alifano, Maria E Mycielska
来源：
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
摘要：
柠檬酸是克雷布斯循环的一个关键代谢产物，也可以在细胞质中转运，发挥多个功能。在正常细胞中，柠檬酸能维持蛋白乙酰化、脂质合成、糖异生、胰岛素分泌、骨组织形成、精子运动以及免疫反应。柠檬酸代谢的失调与多种疾病有关，包括癌症。本文探讨了癌细胞如何利用柠檬酸维持其增殖、存活和转移进展。此外，我们提出了两种相互矛盾的策略，通过靶向柠檬酸代谢来减少肿瘤生长，这在临床前模型中得到证实。第一种策略是在肿瘤微环境中给予大量柠檬酸，其可作为糖酵解抑制剂和诱导凋亡剂，而另一种策略则通过靶向柠檬酸转运蛋白来使癌细胞缺乏柠檬酸。这些策略在多种临床前体外和体内癌症模型中表现出良好的疗效，可以在临床中加以利用，特别是提高对当前抗癌药物的敏感性。版权所有 © 2023 Elsevier B.V. 发布。
Citrate is a key metabolite of the Krebs cycle that can also be exported in the cytosol, where it performs several functions. In normal cells, citrate sustains protein acetylation, lipid synthesis, gluconeogenesis, insulin secretion, bone tissues formation, spermatozoid mobility, and immune response. Dysregulation of citrate metabolism is implicated in several pathologies, including cancer. Here we discuss how cancer cells use citrate to sustain their proliferation, survival, and metastatic progression. Also, we propose two paradoxically opposite strategies to reduce tumour growth by targeting citrate metabolism in preclinical models. In the first strategy, we propose to administer in the tumor microenvironment a high amount of citrate, which can then act as a glycolysis inhibitor and apoptosis inducer, whereas the other strategy targets citrate transporters to starve cancer cells from citrate. These strategies, effective in several preclinical in vitro and in vivo cancer models, could be exploited in clinics, particularly to increase sensibility to current anti-cancer agents.Copyright © 2023. Published by Elsevier B.V.