磷酸甘油酸激酶1在颅内肿瘤中的作用研究进展

Research advances in the role of phosphoglycerate kinase 1 in intracranial tumors

摘要:

磷酸甘油酸激酶1（PGK1）是糖酵解通路中催化首个腺苷三磷酸（ATP）产生的关键酶，在颅内肿瘤（尤其是胶质瘤）驱动代谢重编程中发挥核心作用。其过表达显著增强糖酵解活性（瓦尔堡效应），抑制线粒体氧化磷酸化，满足肿瘤快速增殖的能量与合成前体需求。除经典代谢功能外，PGK1展现出非经典作用机制，作为蛋白激酶通过自磷酸化（如Tyr324位点）激活自身活性，并深度参与肿瘤恶性进展。研究表明，PGK1在胶质瘤细胞中可与β-catenin共定位，通过增强Wnt/β-catenin信号通路促进肿瘤细胞侵袭迁移；其向细胞核等亚结构的转位还可能调控基因转录，加速肿瘤转移进程。PGK1的异常活化是颅内肿瘤治疗抵抗的关键因素，一方面，其表达上调增强自噬活性，帮助肿瘤细胞清除化疗损伤；另一方面，通过O-GlcNAc糖基化修饰动态调节糖酵解与三羧酸循环平衡，导致微环境酸化和乳酸堆积，降低药物递送效率。此外，PGK1还可能通过影响核苷酸合成间接参与脱氧核糖核酸（DNA）修复，削弱放疗敏感性。这些机制共同导致颅内肿瘤对放疗、化疗耐受性增强。作为重要预后标志物，PGK1在星形胶质瘤等颅内肿瘤中的高表达与患者不良生存率相关。其特异性翻译后修饰形式（如自磷酸化pY324-PGK1、精氨酸甲基化meR206-PGK1）的组合检测可进一步提升预后评估精度。在靶向治疗领域，PGK1展现出多重干预潜力，小分子抑制剂通过靶向其激酶结构域有效阻断ATP生成，在临床前模型中抑制肿瘤生长；联合靶向上游调控因子（如抑制蛋白精氨酸甲基转移酶1介导的甲基化或胞外信号调节激酶介导的磷酸化）可间接阻断其功能；此外，靶向肿瘤相关免疫细胞（如肿瘤相关巨噬细胞）中差异表达的PGK1可能重塑免疫抑制微环境，为联合免疫治疗提供新策略。该文旨在阐述PGK1在颅内肿瘤中发生、发展机制的研究进展，为探索颅内肿瘤的治疗提供新思路。

Abstract:

Phosphoglycerate kinase 1 （PGK1） is a key enzyme in the glycolytic pathway that catalyzes the first ATP-generating step， and it plays a core role in intracranial tumors， especially gliomas， by driving metabolic reprogramming. PGK1 overexpression significantly enhances glycolytic activity （known as the Warburg effect） and inhibit mitochondrial oxidative phosphorylation， thereby meeting the demands for energy and biosynthetic precursors during rapid tumor proliferation. Beyond its canonical metabolic functions， PGK1 exhibits the non-canonical mechanisms of acting as a protein kinase to activate itself and promote the progression of malignant tumor through autophosphorylation （e.g.， at the Tyr324 locus）. Studies have shown that PGK1 can be co-localized with β-catenin in glioma cells and promote the invasion and migration of tumor cells by enhancing the Wnt/β-catenin signaling pathway， and its translocation to the subcellular compartments such as the nucleus may also regulate gene transcription and accelerate tumor metastasis. PGK1 dysregulation is a critical factor in therapeutic resistance of intracranial tumors： on the one hand， the upregulated expression of PGK1 enhances autophagy and help tumor cells clear chemotherapy-induced damage； on the other hand， PGK1 disturbs the balance between glycolysis and the tricarboxylic acid cycle through dynamic O-GlcNAc glycosylation， thereby leading to microenvironment acidification and lactate accumulation and reducing drug delivery efficiency； furthermore， PGK1 may indirectly participate in DNA repair by influencing nucleotide synthesis， thereby reducing radiosensitivity. These mechanisms collectively enhance tumor tolerance to radiotherapy and chemotherapy. As an important prognostic biomarker， PGK1 is highly expressed in astrocytomas and other intracranial tumors， which is correlated with the poor survival rates of patients. Combined detection of specific post-translational modifications of PGK1， such as autophosphorylation （pY324-PGK1） and arginine methylation （meR206-PGK1）， can further improve the accuracy of prognostic assessment. In the realm of targeted therapy， PGK1 presents multifaceted intervention potential： small-molecule inhibitors effectively block ATP generation by targeting its kinase domain and inhibit tumor growth in preclinical models； combined targeting of upstream regulators （e.g.， inhibiting PRMT1-mediated methylation or ERK-mediated phosphorylation） offers indirect strategies to disrupt its function； in addition， targeting differentially expressed PGK1 within tumor-associated immune cells， such as tumor-associated macrophages， can reshape the immunosuppressive microenvironment and provide new strategies for combined immunotherapy. This article reviews the research advances in the mechanisms of action of PGK1 in the pathogenesis and progression of intracranial tumors， in order to provide new insights for exploring the treatment of intracranial tumors.