Abstract

Growing cells increase multiple biosynthetic processes in response to the high metabolic demands needed to sustain proliferation. The even higher metabolic requirements in the setting of cancer provoke proportionately greater biosynthesis. Underappreciated key aspects of this increased metabolic demand are guanine nucleotides and adaptive mechanisms to regulate their concentration. Using the malignant brain tumour, glioblastoma, as a model, we have demonstrated that one of the rate-limiting enzymes for guanosine triphosphate (GTP) synthesis, inosine monophosphate dehydrogenase-2 (IMPDH2), is increased and IMPDH2 expression is necessary for the activation of de novo GTP biosynthesis. Moreover, increased IMPDH2 enhances RNA polymerase I and III transcription directly linking GTP metabolism to both anabolic capacity as well as nucleolar enlargement historically observed as associated with cancer. In this review, we will review in detail the basis of these new discoveries and, more generally, summarize the current knowledge on the role of GTP metabolism in cancer.

中文翻译：

---

IMPDH2进行的GTP代谢重编程：释放癌细胞的加油机制。

摘要

生长的细胞响应维持增殖所需的高代谢需求而增加了多个生物合成过程。在癌症环境中更高的代谢要求会相应地激发更大的生物合成。这种增加的代谢需求的未被充分认识的关键方面是鸟嘌呤核苷酸和调节其浓度的适应性机制。使用恶性脑肿瘤胶质母细胞瘤作为模型，我们证明了鸟苷三磷酸（GTP）合成的限速酶之一，肌苷单磷酸脱氢酶-2（IMPDH2）增加，并且激活需要IMPDH2表达的从头GTP生物合成。此外，增加的IMPDH2增强RNA聚合酶I和III转录，这直接将GTP代谢与合成代谢能力以及历史上与癌症相关的核仁增大联系在一起。在这篇综述中，我们将详细回顾这些新发现的基础，并且更概括地说，总结有关GTP代谢在癌症中作用的最新知识。