肿瘤中TP53诱导的糖酵解和凋亡调节因子及其靶向治疗研究进展

Advances in TP53-induced glycolysis and apoptosis regulator in tumor and its targeted therapy

TP53诱导的糖酵解和凋亡调节因子(TP53-induced glycolysis and apoptosis regulator,TIGAR)是p53下游的直接靶基因,其编码蛋白能够降解2,6-二磷酸果糖,后者是肿瘤细胞糖酵解途径中关键酶6-磷酸果糖激酶1(6-phosphofructokinase 1,PFK1)的最强激活剂,从而对糖酵解产生抑制作用。TIGAR可促使糖代谢更多地流向磷酸戊糖途径(pentose phosphate pathway,PPP),促进烟酰胺腺嘌呤二核苷酸磷酸(nicotinamide adenine dinucleotide phosphate,NADPH)和谷胱甘肽(glutathione,GSH)的产生,降低细胞内活性氧(reactive oxygen species,ROS)水平。因此,TIGAR是维持肿瘤细胞氧化还原状态平衡的重要因子,对细胞凋亡起到重要的调节作用。最新研究表明,TIGAR在肿瘤发生、进展及转移过程中发挥重要作用,而且干扰TIGAR表达可以提高多种肿瘤细胞对放化疗的敏感性,提示TIGAR可能成为一个极具潜力的肿瘤治疗靶点。本文对近年来TIGAR在肿瘤发生、进展和转移中的作用以及其靶向治疗的研究进展进行简要综述。

TP53-induced glycolysis and apoptosis regulator （TIGAR） is a p53- inducible target gene. TIGAR-encoding protein can inhibit glycolysis through reducing the intracellular level of fructose-2,6-bisphosphate which is the strongest activator of 6-phosphofructokinase 1 （PFK1）, because PRK1 is a key enzyme in glycolytic pathway of tumor cells. TIGAR can promote glucose metabolism more to the pentose phosphate pathway （PPP）, increase the productions of nicotinamide adenine dinucleotide phosphate （NADPH） and glutathione （GSH）, and reduce the level of intracellular reactive oxygen species （ROS）. Therefore, TIGAR is an important factor to maintain the homeostasis status of redox, and to regulate apoptosis of tumor cells. Recent studies showed that TIGAR plays an important role in tumorigenesis, progression and metastasis process. Moreover, the interference of TIGAR gene expression can enhance the radiosensitivity and chemosensitivity of many kinds of tumor cells, suggesting that TIGAR may become a potential target for the treatment of tumor. This article reviews the latest advances in the role of TIGAR in tumorigenesis, progression, metastasis and its targeted therapy.