Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
Cell Rep. 2019 Sep 3;28(10):2608-2619.e6. doi: 10.1016/j.celrep.2019.07.098.
Hepatocellular carcinoma (HCC) is a devastating cancer increasingly caused by non-alcoholic fatty liver disease (NAFLD). Disrupting the liver Mitochondrial Pyruvate Carrier (MPC) in mice attenuates NAFLD. Thus, we considered whether liver MPC disruption also prevents HCC. Here, we use the N-nitrosodiethylamine plus carbon tetrachloride model of HCC development to test how liver-specific MPC knock out affects hepatocellular tumorigenesis. Our data show that liver MPC ablation markedly decreases tumorigenesis and that MPC-deficient tumors transcriptomically downregulate glutathione metabolism. We observe that MPC disruption and glutathione depletion in cultured hepatomas are synthetically lethal. Stable isotope tracing shows that hepatocyte MPC disruption reroutes glutamine from glutathione synthesis into the tricarboxylic acid (TCA) cycle. These results support a model where inducing metabolic competition for glutamine by MPC disruption impairs hepatocellular tumorigenesis by limiting glutathione synthesis. These findings raise the possibility that combining MPC disruption and glutathione stress may be therapeutically useful in HCC and additional cancers.
肝细胞癌 (HCC) 是一种破坏性癌症，越来越多地由非酒精性脂肪性肝病 (NAFLD) 引起。在小鼠中破坏肝脏线粒体丙酮酸载体 (MPC) 可减轻 NAFLD。因此，我们考虑肝脏 MPC 破坏是否也能预防 HCC。在这里，我们使用 N-亚硝基二乙胺加四氯化碳 HCC 发展模型来测试肝特异性 MPC 敲除如何影响肝细胞肿瘤发生。我们的数据表明，肝脏 MPC 缺失显着降低肿瘤发生，并且 MPC 缺陷型肿瘤在转录水平下调谷胱甘肽代谢。我们观察到培养的肝癌细胞中 MPC 破坏和谷胱甘肽耗竭是合成致死的。稳定同位素示踪表明，肝细胞 MPC 破坏将谷氨酰胺从谷胱甘肽合成重新定向到三羧酸 (TCA) 循环。这些结果支持这样一种模型，即通过 MPC 破坏诱导对谷氨酰胺的代谢竞争，通过限制谷胱甘肽合成来损害肝细胞肿瘤发生。这些发现提出了一种可能性，即联合 MPC 破坏和谷胱甘肽应激可能在 HCC 和其他癌症的治疗中具有潜在的应用价值。
