Background

Nucleotide metabolism is a critical pathway that generates purine and pyrimidine molecules for DNA replication, RNA synthesis, and cellular bioenergetics. Increased nucleotide metabolism supports uncontrolled growth of tumors and is a hallmark of cancer. Agents inhibiting synthesis and incorporation of nucleotides in DNA are widely used as chemotherapeutics to reduce tumor growth, cause DNA damage, and induce cell death. Thus, the research on nucleotide metabolism in cancer is primarily focused on its role in cell proliferation. However, in addition to proliferation, the role of purine molecules is established as ligands for purinergic signals. However, so far, the role of the pyrimidines has not been discussed beyond cell growth.

Scope of the review

In this review we present the key evidence from recent pivotal studies supporting the notion of a non-proliferative role for pyrimidine metabolism (PyM) in cancer, with a special focus on its effect on differentiation in cancers from different origins.

Major conclusion

In leukemic cells, the pyrimidine catabolism induces terminal differentiation toward monocytic lineage to check the aberrant cell proliferation, whereas in some solid tumors (e.g., triple negative breast cancer and hepatocellular carcinoma), catalytic degradation of pyrimidines maintains the mesenchymal-like state driven by epithelial-to-mesenchymal transition (EMT). This review further broadens this concept to understand the effect of PyM on metastasis and, ultimately, delivers a rationale to investigate the involvement of the pyrimidine molecules as oncometabolites. Overall, understanding the non-proliferative role of PyM in cancer will lead to improvement of the existing antimetabolites and to development of new therapeutic options.

中文翻译：

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嘧啶代谢在癌症中的非增殖作用。

背景

核苷酸代谢是产生嘌呤和嘧啶分子以进行DNA复制，RNA合成和细胞生物能的关键途径。核苷酸代谢增加支持肿瘤不受控制的生长，是癌症的标志。抑制核苷酸合成和掺入DNA的药物被广泛用作化学治疗剂，以减少肿瘤的生长，引起DNA损伤并诱导细胞死亡。因此，关于癌症中核苷酸代谢的研究主要集中于其在细胞增殖中的作用。然而，除了增殖以外，嘌呤分子的作用被确立为嘌呤能信号的配体。但是，到目前为止，除细胞生长外，尚未讨论嘧啶的作用。

审查范围

在这篇综述中，我们提供了来自近期关键性研究的关键证据，这些证据支持嘧啶代谢（PyM）在癌症中具有非增殖作用的观点，特别关注其对不同来源的癌症分化的影响。

主要结论

在白血病细胞中，嘧啶分解代谢诱导向单核细胞系的终末分化，以检查异常细胞增殖，而在某些实体瘤（例如三阴性乳腺癌和肝细胞癌）中，嘧啶的催化降解维持上皮驱动的间充质样状态向间质转化（EMT）。这项审查进一步拓宽了这一概念，以了解PyM对转移的影响，并最终为研究嘧啶分子作为代谢物的参与提供了理论依据。总体而言，了解PyM在癌症中的非增殖作用将导致现有抗代谢物的改善和新治疗方法的开发。