Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
Cancer Biology Program, Stanford University School of Medicine, Stanford, California.
Mol Cancer Res. 2023 Oct 2;21(10):1010-1016. doi: 10.1158/1541-7786.MCR-23-0049.
When the electron transport chain (ETC) function is impaired, cancer cells rely on reductive carboxylation (RC) to convert α-ketoglutarate (αKG) to citrate for macromolecular synthesis, thereby promoting tumor growth. Currently, there is no viable therapy to inhibit RC for cancer treatment. In this study, we demonstrate that the mitochondrial uncoupler treatment effectively inhibits RC in cancer cells. Mitochondrial uncoupler treatment activates the ETC and increases the NAD+/NADH ratio. Using U-13C-glutamine and 1-13C-glutamine tracers, we show that mitochondrial uncoupling accelerates the oxidative tricarboxylic acid (TCA) cycle and blocks RC under hypoxia, in von Hippel-Lindau (VHL) tumor suppressor-deficient kidney cancer cells, or under anchorage-independent growth condition. Together, these data demonstrate that mitochondrial uncoupling redirects α-KG from RC back to the oxidative TCA cycle, highlighting that the NAD+/NADH ratio is one key switch that determines the metabolic fate of α-KG. Inhibiting RC could be a key mechanism by which mitochondrial uncouplers inhibit tumor growth.
Mitochondrial uncoupling is a novel strategy to target RC in cancer.
当电子传递链（ETC）功能受损时，癌细胞依赖还原性羧化作用（RC）将α-酮戊二酸（αKG）转化为柠檬酸，用于大分子合成，从而促进肿瘤生长。目前，尚无可行的疗法来抑制 RC 以治疗癌症。在这项研究中，我们证明了线粒体解偶联剂治疗可有效抑制癌细胞中的 RC。线粒体解偶联剂治疗可激活 ETC 并增加 NAD+/NADH 比值。使用 U-13C-谷氨酰胺和 1-13C-谷氨酰胺示踪剂，我们表明在线粒体解偶联下，缺氧、抑癌基因 von Hippel-Lindau（VHL）缺陷的肾癌细胞或无锚定生长条件下，RC 被加速的氧化三羧酸（TCA）循环和阻断。总之，这些数据表明，线粒体解偶联将 α-KG 从 RC 重新引导回氧化 TCA 循环，这突出表明 NAD+/NADH 比值是决定 α-KG 代谢命运的关键开关之一。抑制 RC 可能是线粒体解偶联剂抑制肿瘤生长的关键机制。
线粒体解偶联是一种针对癌症中 RC 的新策略。
