UCP2 Deficiency Increases Colon Tumorigenesis by Promoting Lipid Synthesis and Depleting NADPH for Antioxidant Defenses
UCP2 Deficiency Increases Colon Tumorigenesis by Promoting Lipid Synthesis and Depleting NADPH for Antioxidant Defenses
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DOI：
10.1016/j.celrep.2019.07.097
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发表时间：
2019-08-27
期刊：
影响因子：
8.8
通讯作者：
Alves-Guerra, Marie-Clotilde
中科院分区：
文献类型：
--
作者：
Aguilar, Esther;Esteves, Pauline;Alves-Guerra, Marie-Clotilde
结直肠癌（CRC）与代谢和氧化还原干扰有关。线粒体转运体解偶联蛋白2（UCP 2）通过调节细胞代谢来控制体外细胞增殖，但体内肿瘤的潜在机制尚未探索。使用小鼠肠癌模型和CRC患者样本，我们发现肿瘤中的UCP 2蛋白水平高于非肿瘤对应物。我们揭示了UCP 2的肿瘤抑制作用，因为它的缺失分别增强了AOM/DSS治疗和Apc（Min/+）小鼠中的结肠和小肠肿瘤发生，并且与后一种模型中的存活率差相关。从机制上讲，UCP 2的丢失增加了肿瘤中氧化型谷胱甘肽和蛋白质的水平。UCP 2缺乏改变糖酵解途径，同时促进磷脂合成，从而限制NADPH缓冲氧化应激的可用性。我们发现，UCP 2的丢失使结肠细胞更容易通过代谢重编程和氧化还原稳态的扰动而发生恶性转化，并可能有利于CRC的预后。
Colorectal cancer (CRC) is associated with metabolic and redox perturbation. The mitochondrial transporter uncoupling protein 2 (UCP2) controls cell proliferation in vitro through the modulation of cellular metabolism, but the underlying mechanism in tumors in vivo remains unexplored. Using murine intestinal cancer models and CRC patient samples, we find higher UCP2 protein levels in tumors compared to their non-tumoral counterparts. We reveal the tumor-suppressive role of UCP2 as its deletion enhances colon and small intestinal tumorigenesis in AOM/DSS-treated and Apc(Min/+) mice, respectively, and correlates with poor survival in the latter model. Mechanistically, UCP2 loss increases levels of oxidized glutathione and proteins in tumors. UCP2 deficiency alters glycolytic pathways while promoting phospholipid synthesis, thereby limiting the availability of NADPH for buffering oxidative stress. We show that UCP2 loss renders colon cells more prone to malignant transformation through metabolic reprogramming and perturbation of redox homeostasis and could favor worse outcomes in CRC.