Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospitals, Coventry CV2 2DX, UK; Warwick Systems Biology Centre, Senate House, University of Warwick, Coventry CV4 7AL, UK.
Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospitals, Coventry CV2 2DX, UK.
Semin Cancer Biol. 2018 Apr;49:83-93. doi: 10.1016/j.semcancer.2017.05.006. Epub 2017 May 12.
Glyoxalase 1 (Glo1) is part of the glyoxalase system in the cytoplasm of all human cells. It catalyses the glutathione-dependent removal of the endogenous reactive dicarbonyl metabolite, methylglyoxal (MG). MG is formed mainly as a side product of anaerobic glycolysis. It modifies protein and DNA to form mainly hydroimidazolone MG-H1 and imidazopurinone MGdG adducts, respectively. Abnormal accumulation of MG, dicarbonyl stress, increases adduct levels which may induce apoptosis and replication catastrophe. In the non-malignant state, Glo1 is a tumour suppressor protein and small molecule inducers of Glo1 expression may find use in cancer prevention. Increased Glo1 expression is permissive for growth of tumours with high glycolytic activity and is thereby a biomarker of tumour growth. High Glo1 expression is a cause of multi-drug resistance. It is produced by over-activation of the Nrf2 pathway and GLO1 amplification. Glo1 inhibitors are antitumour agents, inducing apoptosis and necrosis, and anoikis. Tumour stem cells and tumours with high flux of MG formation and Glo1 expression are sensitive to Glo1 inhibitor therapy. It is likely that MG-induced cell death contributes to the mechanism of action of current antitumour agents. Common refractory tumours have high prevalence of Glo1 overexpression for which Glo1 inhibitors may improve therapy.
甘油醛 1（Glo1）是所有人体细胞细胞质中甘油醛酶系统的一部分。它催化谷胱甘肽依赖性去除内源性反应性二羰基代谢物甲基乙二醛（MG）。MG 主要作为无氧糖酵解的副产物形成。它修饰蛋白质和 DNA，分别形成主要的氢咪唑酮 MG-H1 和咪唑嘌呤酮 MGdG 加合物。MG 的异常积累、二羰基应激增加加合物水平，可能诱导细胞凋亡和复制灾难。在非恶性状态下，Glo1 是一种肿瘤抑制蛋白，Glo1 表达的小分子诱导剂可能在癌症预防中找到用途。增加的 Glo1 表达允许具有高糖酵解活性的肿瘤生长，因此是肿瘤生长的生物标志物。高 Glo1 表达是多药耐药的原因。它是由 Nrf2 途径的过度激活和 GLO1 扩增引起的。Glo1 抑制剂是抗肿瘤剂，诱导细胞凋亡和坏死以及失巢凋亡。肿瘤干细胞和具有高 MG 形成和 Glo1 表达通量的肿瘤对 Glo1 抑制剂治疗敏感。MG 诱导的细胞死亡可能是当前抗肿瘤药物作用机制的原因。常见的难治性肿瘤普遍存在 Glo1 过表达，Glo1 抑制剂可能改善其治疗效果。
