Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
J Mol Endocrinol. 2020 Nov;65(4):R77-R90. doi: 10.1530/JME-20-0176.
Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. Early studies identified ME1 as a mediator of intermediary metabolism primarily through its participatory roles in lipid and cholesterol biosynthesis. ME1 was one of the first identified insulin-regulated genes in liver and adipose and is a transcriptional target of thyroxine. Multiple studies have since documented that ME1 is pro-oncogenic in numerous epithelial cancers. In tumor cells, the reduction of ME1 gene expression or the inhibition of its activity resulted in decreases in proliferation, epithelial-to-mesenchymal transition and in vitro migration, and conversely, in promotion of oxidative stress, apoptosis and/or cellular senescence. Here, we integrate recent findings to highlight ME1's role in oncogenesis, provide a rationale for its nexus with metabolic syndrome and diabetes, and raise the prospects of targeting the cytosolic NADPH network to improve therapeutic approaches against multiple cancers.
苹果酸酶 1（ME1）是一种细胞溶质蛋白，可催化苹果酸转化为丙酮酸，同时将 NADP 转化为 NADPH。早期研究将 ME1 鉴定为中间代谢物的介质，主要通过其在脂质和胆固醇生物合成中的参与作用。ME1 是肝脏和脂肪组织中最早被鉴定为胰岛素调节基因之一，也是甲状腺素的转录靶标。此后，多项研究表明，ME1 在多种上皮性癌中具有致癌作用。在肿瘤细胞中，降低 ME1 基因表达或抑制其活性会导致增殖、上皮-间充质转化和体外迁移减少，相反，会促进氧化应激、细胞凋亡和/或细胞衰老。在这里，我们整合了最近的发现，强调 ME1 在致癌中的作用，为其与代谢综合征和糖尿病的关系提供理论依据，并提出靶向细胞溶质 NADPH 网络以改善针对多种癌症的治疗方法的前景。
