Cuthbertson Christine R, Arabzada Zahra, Bankhead Armand, Kyani Armita, Neamati Nouri
Department of Medicinal Chemistry, College of Pharmacy and the Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan 48109, United States.
ACS Pharmacol Transl Sci. 2021 Mar 1;4(2):624-646. doi: 10.1021/acsptsci.0c00223. eCollection 2021 Apr 9.
Metabolic reprogramming is a key hallmark of cancer and shifts cellular metabolism to meet the demands of biomass production necessary for abnormal cell reproduction. One-carbon metabolism (1CM) contributes to many biosynthetic pathways that fuel growth and is comprised of a complex network of enzymes. Methotrexate and 5-fluorouracil were pioneering drugs in this field and are still widely used today as anticancer agents as well as for other diseases such as arthritis. Besides dihydrofolate reductase and thymidylate synthase, two other enzymes of the folate cycle arm of 1CM have not been targeted clinically: serine hydroxymethyltransferase (SHMT) and methylenetetrahydrofolate dehydrogenase (MTHFD). An increasing body of literature suggests that the mitochondrial isoforms of these enzymes (SHMT2 and MTHFD2) are clinically relevant in the context of cancer. In this review, we focused on the 1CM pathway as a target for cancer therapy and, in particular, SHMT2 and MTHFD2. The function, regulation, and clinical relevance of SHMT2 and MTHFD2 are all discussed. We expand on previous clinical studies and evaluate the prognostic significance of these critical enzymes by performing a pan-cancer analysis of patient data from the The Cancer Genome Atlas and a transcriptional coexpression network enrichment analysis. We also provide an overview of preclinical and clinical inhibitors targeting the folate pathway, the methionine cycle, and folate-dependent purine biosynthesis enzymes.
代谢重编程是癌症的一个关键特征，它会改变细胞代谢，以满足异常细胞增殖所需的生物量生产需求。一碳代谢（1CM）为许多促进生长的生物合成途径做出贡献，由一个复杂的酶网络组成。甲氨蝶呤和5-氟尿嘧啶是该领域的先驱药物，如今仍作为抗癌药物以及用于治疗关节炎等其他疾病而被广泛使用。除了二氢叶酸还原酶和胸苷酸合成酶外，1CM叶酸循环分支中的另外两种酶尚未成为临床治疗靶点：丝氨酸羟甲基转移酶（SHMT）和亚甲基四氢叶酸脱氢酶（MTHFD）。越来越多的文献表明，这些酶的线粒体异构体（SHMT2和MTHFD2）在癌症背景下具有临床相关性。在本综述中，我们重点关注1CM途径作为癌症治疗靶点，特别是SHMT2和MTHFD2。讨论了SHMT2和MTHFD2的功能、调节及其临床相关性。我们扩展了先前的临床研究，并通过对来自癌症基因组图谱的患者数据进行泛癌分析和转录共表达网络富集分析，评估这些关键酶的预后意义。我们还概述了针对叶酸途径、甲硫氨酸循环和叶酸依赖性嘌呤生物合成酶的临床前和临床抑制剂。
