Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08540, USA; Department of Chemistry, Princeton University, Princeton, NJ 08540, USA.
Cell Metab. 2021 Jan 5;33(1):94-109.e8. doi: 10.1016/j.cmet.2020.10.002. Epub 2020 Nov 6.
The emergence of cancer from diverse normal tissues has long been rationalized to represent a common set of fundamental processes. However, these processes are not fully defined. Here, we show that forced expression of glucose-6-phosphate dehydrogenase (G6PD) affords immortalized mouse and human cells anchorage-independent growth in vitro and tumorigenicity in animals. Mechanistically, G6PD augments the NADPH pool by stimulating NAD kinase-mediated NADP biosynthesis in addition to converting NADP to NADPH, bolstering antioxidant defense. G6PD also increases nucleotide precursor levels through the production of ribose and NADPH, promoting cell proliferation. Supplementation of antioxidants or nucleosides suffices to convert immortalized mouse and human cells into a tumorigenic state, and supplementation of both is required when their overlapping metabolic consequences are minimized. These results suggest that normal cells have a limited capacity for redox balance and nucleotide synthesis, and overcoming this limit might represent a key aspect of oncogenic transformation.
从不同的正常组织中出现癌症长期以来被认为代表了一组共同的基本过程。然而，这些过程并没有被完全定义。在这里，我们表明，葡萄糖-6-磷酸脱氢酶（G6PD）的强制表达赋予了永生的小鼠和人类细胞体外的无锚定生长能力，并在动物中具有致瘤性。从机制上讲，G6PD 通过刺激 NAD 激酶介导的 NADP 生物合成来增加 NADPH 池，除了将 NADP 转化为 NADPH 之外，还增强了抗氧化防御。G6PD 还通过产生核糖和 NADPH 来增加核苷酸前体水平，促进细胞增殖。抗氧化剂或核苷的补充足以将永生的小鼠和人类细胞转化为致瘤状态，当它们重叠的代谢后果最小化时，两者的补充都是必需的。这些结果表明，正常细胞的氧化还原平衡和核苷酸合成能力有限，克服这一限制可能是致癌转化的一个关键方面。
