Targeting the methionine-methionine adenosyl transferase 2A- S -adenosyl methionine axis for cancer therapy.
Targeting the methionine-methionine adenosyl transferase 2A- S -adenosyl methionine axis for cancer therapy.
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DOI：
10.1097/cco.0000000000000870
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发表时间：
2022-09-01
影响因子：
3.4
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中科院分区：
文献类型：
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本文就甲硫氨酸、甲硫氨酸腺苷转移酶2A（MAT 2A）和S-腺苷甲硫氨酸（SAM）在肿瘤发生过程中甲基化反应中的生物学作用作一综述。新出现的抑制剂靶向蛋氨酸-MAT 2A-SAM轴将进行讨论。SAM是调节基因表达的甲基化反应的关键和全局甲基供体，在哺乳动物细胞中，它由MAT 2A使用甲硫氨酸合成。最近的研究已经验证了蛋氨酸和MAT 2A作为癌细胞的代谢依赖性，因为它们在SAM生物合成中起重要作用。MAT 2A抑制导致甲硫腺苷磷酸化酶（MTAP）缺失的癌症中的合成致死性，其占所有癌症类型的15%。值得注意的是，随着一流的MAT 2A抑制剂AG-270和IDE 397进入治疗癌症的临床试验，在开发针对甲硫氨酸-MAT 2A-SAM轴的抑制剂方面取得了显着进展。蛋氨酸-MAT 2A-SAM轴通过提供SAM作为癌细胞中异常蛋白质以及DNA和RNA甲基化的关键底物而在肿瘤发生中起重要作用。通过MAT 2A抑制靶向SAM生物合成已成为癌症治疗的新的和有前途的策略。
In this review, we summarize the biological roles of methionine, methionine adenosyl transferase 2A (MAT2A) and S-adenosyl methionine (SAM) in methylation reactions during tumorigenesis. Newly emerged inhibitors targeting the Methionine-MAT2A-SAM axis will be discussed. SAM is the critical and global methyl-donor for methylation reactions regulating gene expression, and in mammalian cells, it is synthesized by MAT2A using methionine. Recent studies have validated methionine and MAT2A as metabolic dependencies of cancer cells because of their essential roles in SAM biosynthesis. MAT2A inhibition leads to synthetic lethality in methylthioadenosine-phosphorylase (MTAP)-deleted cancers, which accounts for 15% of all cancer types. Of note, remarkable progress has been made in developing inhibitors targeting the Methionine-MAT2A-SAM axis, as the first-in-class MAT2A inhibitors AG-270 and IDE397 enter clinical trials to treat cancer. The Methionine-MAT2A-SAM axis plays an important role in tumorigenesis by providing SAM as a critical substrate for abnormal protein as well as DNA and RNA methylation in cancer cells. Targeting SAM biosynthesis through MAT2A inhibition has emerged as a novel and promising strategy for cancer therapy.