肿瘤中甲硫氨酸代谢及其相关基因的表达调控

甲硫氨酸(methionine)作为人体必需氨基酸,生理功能多样,在肿瘤代谢重编程过程中具有重要意义。研究发现,多种肿瘤细胞对外源性甲硫氨酸存在依赖性,该效应被称为Hoffman效应。在人体内,甲硫氨酸经甲硫氨酸循环代谢,参与一碳单位代谢、叶酸循环,以及多胺、谷胱甘肽、半胱氨酸和核苷酸等多种物质的合成。肿瘤中常出现甲硫氨酸代谢的改变,并伴随甲硫氨酸代谢相关酶基因表达的异常,其中以甲硫氨酸腺苷转移酶(methionine adenosyltransferase, MAT)相关基因表达改变及甲硫腺苷磷酸化酶(methylthioadenosine phosphorylase,MTAP)基因的缺失最为常见,二者可分别引起甲硫氨酸循环及甲硫氨酸补救合成途径的异常,进而导致甲基供体S-腺苷甲硫氨酸(S-adenosylmethionine, SAM)的生成减少和甲硫腺苷(methylthioadenosine, MTA)的堆积,其与肿瘤的发生、发展和转移等活动密切相关。由甲硫氨酸的代谢改变和代谢酶的基因表达异常,分别衍生出2种不同的治疗策略,即甲硫氨酸限制疗法和靶向治疗。本文将从甲硫氨酸代谢出发,阐述肿瘤中甲硫氨酸依懒性、肿瘤细胞MAT和MTAP相关基因的表达调控,并概述甲硫氨酸相关肿瘤治疗方案的新进展与新问题,为肿瘤治疗方案的进一步探索提供新思路。

Methionine Metabolism and Related Gene Expression Regulation in Cancers

Methionine, an essential amino acid with a variety of physiological functions, plays an important role in the process of metabolic reprogramming of cancer cells. A large number of studies have found that there is dependence on exogenous methionine in different kinds of cancer cells, which is called the Hoffman effect. In vivo, methionine is metabolized through the methionine cycle, linking with the one carbon unit metabolism, folate cycle and the synthesis of many substances such as polyamine, glutathione, cysteine and nucleotide. Abnormity of methionine metabolism often occurs in tumors, accompanied by abnormal gene expression of methionine metabolism related enzymes, including methionine adenosyltransferase (MAT) and methylthioadenosine phosphorylase (MTAP). The abnormal expression of MAT and MTAP can lead to the abnormity of methionine cycle and the salvage pathway, resulting in the decrease of methyl donor S-adenosylmethionine (SAM) and the accumulation of methylthioadenosine (MTA) in cancer cells, which is associated with the genesis, progression and metastasis of tumors. Methionine restriction and target therapy derive from the changes of methionine metabolism and related gene expression separately. This review summarizes the changes of methionine-dependent metabolism and the expression regulation of methionine metabolism related genes in cancer cells. Also, the new progress and difficulty in methionine-related cancer therapy is introduced. This review may provide new clues for the exploration of cancer therapy.