Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors.
Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors.
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DOI：
10.3390/cells10112913
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发表时间：
2021-10-27
期刊：
影响因子：
6
通讯作者：
Chittiboina P
中科院分区：
文献类型：
--
作者：
Alvarez R;Mandal D;Chittiboina P
PFKFB3是一种双功能酶，调节和维持细胞内果糖-2，6-二磷酸(F2，6-P2)的浓度，本质上控制糖酵解的速度。PFKFB3是已知的肿瘤细胞中糖酵解重连的激活剂，包括中枢神经系统(CNS)肿瘤细胞。PFKFB3的病理调控是通过各种微环境刺激和致癌信号来实现的。低氧是通过HIF-1α诱导PFKFB3转录的主要因素。此外，PFKFB3的翻译修饰是由各种细胞内信号通路驱动的，这些信号通路允许PFKFB3对不同的刺激做出反应。PFKFB3通过F6P与来自ATP的供体PO4基团的磷酸化来合成F2，6P2，是所有PFKFB同工酶中具有最高活性的。肿瘤细胞内F2，6P2的浓度主要由PFKFB3维持，允许癌细胞逃避糖酵解抑制。PFKFB3是负责糖酵解肿瘤代谢重编程的主要酶。在高级别胶质瘤中，PFKFB3蛋白水平显著高于非病理性脑组织或低级别胶质瘤，但没有相对上调的转录水平。在脑肿瘤中，PFKFB3的高表达与生存不良有关。单独或伴随的PFKFB3抑制在恢复耐药脑肿瘤的化疗敏感性和放射敏感性方面显示出巨大的潜力。对PFKFB3的规范和非规范功能的更好的理解可以允许开发有效的脑肿瘤的联合靶向治疗。
PFKFB3 is a bifunctional enzyme that modulates and maintains the intracellular concentrations of fructose-2,6-bisphosphate (F2,6-P2), essentially controlling the rate of glycolysis. PFKFB3 is a known activator of glycolytic rewiring in neoplastic cells, including central nervous system (CNS) neoplastic cells. The pathologic regulation of PFKFB3 is invoked via various microenvironmental stimuli and oncogenic signals. Hypoxia is a primary inducer of PFKFB3 transcription via HIF-1alpha. In addition, translational modifications of PFKFB3 are driven by various intracellular signaling pathways that allow PFKFB3 to respond to varying stimuli. PFKFB3 synthesizes F2,6P2 through the phosphorylation of F6P with a donated PO4 group from ATP and has the highest kinase activity of all PFKFB isoenzymes. The intracellular concentration of F2,6P2 in cancers is maintained primarily by PFKFB3 allowing cancer cells to evade glycolytic suppression. PFKFB3 is a primary enzyme responsible for glycolytic tumor metabolic reprogramming. PFKFB3 protein levels are significantly higher in high-grade glioma than in non-pathologic brain tissue or lower grade gliomas, but without relative upregulation of transcript levels. High PFKFB3 expression is linked to poor survival in brain tumors. Solitary or concomitant PFKFB3 inhibition has additionally shown great potential in restoring chemosensitivity and radiosensitivity in treatment-resistant brain tumors. An improved understanding of canonical and non-canonical functions of PFKFB3 could allow for the development of effective combinatorial targeted therapies for brain tumors.
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