PDF(Pubmed)
Abstract：
Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NADPH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer mouse models, we show that G6PD ablation significantly suppresses KrasG12D/+;Lkb1-/- (KL) but not KrasG12D/+;P53-/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics reveal that G6PD ablation significantly impairs NADPH generation, redox balance, and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation activates p53, suppressing tumor growth. As tumors progress, G6PD-deficient KL tumors increase an alternative NADPH source from serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations.
摘要：
癌细胞依赖于烟酰胺腺嘌呤二核苷酸磷酸(NADPH)来对抗氧化应激并支持还原性生物合成。一个主要的NADPH生产途径是氧化戊糖磷酸途径（关键步骤：葡萄糖-6-磷酸脱氢酶，G6PD)。替代方案存在并且可以在一些肿瘤中补偿。这里,使用基因工程肺癌小鼠模型，我们显示G6PD消融显著抑制KrasG12D/+;Lkb1-/-(KL),但不抑制KrasG12D/+;P53-/-(KP)肺肿瘤发生。体内同位素示踪和代谢组学表明，G6PD消融显着损害NADPH的产生，氧化还原平衡，KL而不是KP肺肿瘤中的从头脂肪生成。机械上,在KL肿瘤中，G6PD消融激活p53,抑制肿瘤生长。随着肿瘤的进展,G6PD缺陷的KL肿瘤增加了丝氨酸驱动的单碳代谢的替代NADPH来源，使相关的肿瘤来源的细胞系对丝氨酸/甘氨酸消耗敏感。因此，致癌驱动突变决定了肺癌对G6PD的依赖性，其靶向是具有KRAS和LKB1共突变的肿瘤的潜在治疗策略。
