FBP1-Altered Carbohydrate Metabolism Reduces Leukemic Viability through Activating P53 and Modulating the Mitochondrial Quality Control System In Vitro.
FBP1-Altered Carbohydrate Metabolism Reduces Leukemic Viability through Activating P53 and Modulating the Mitochondrial Quality Control System In Vitro.
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fbp1改变碳水化合物代谢通过激活P53和调节线粒体质量控制系统降低白血病生存能力
DOI：
10.3390/ijms231911387
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发表时间：
2022-09-27
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
急性髓性白血病（AML）是成人血癌中最常见的形式，其特点是机制和疾病进展的异质性。开发一种针对未成熟白血病细胞（原细胞）代谢稳态和能量产生的有效治疗策略对于克服不同亚型AML患者的复发和改善预后至关重要。在代谢调节方面，果糖-1,6-二磷酸酶1 （FBP1）是一种糖异生酶，对碳水化合物代谢至关重要，因为糖异生是产生重要代谢物和维持正常细胞活动所必需的能量的中心途径。除了它的催化活性外，FBP1还能抑制癌细胞中的有氧糖酵解——被称为“Warburg效应”。重要的是，虽然FBP1的下调与人体主要器官的癌变有关，但癌细胞中FBP1的恢复促进了细胞凋亡，并阻止了实体瘤的疾病进展。最近，我们的大规模测序分析显示，FBP1是体外MV4-11或MOLM-14胚中17757个维生素d应答基因中的一个新的可诱导治疗靶点，这两种基因都来自FLT3突变的AML患者。为了研究FBP1的抗白血病功能，我们在体外通过慢病毒过表达FBP1转基因（命名为FBP1- mv4 -11）产生了一种新的AML细胞系。结果表明，FBP1-MV4-11细胞比MV4-11细胞更容易发生凋亡。体外P53启动子实验证实，FBP1-MV4-11细胞在机制上显著增加了P53基因和蛋白的表达。然而，体外添加糖酵解后代谢物可以逆转FBP1-MV4-11细胞死亡的增强和增殖的减少。此外，FBP1-MV4-11细胞通过降低细胞色素c氧化酶亚基2 （COX2或MT-CO2）和上调pten诱导的激酶（PINK1）表达，发现线粒体稳态受损。总之，这是第一个体外证据，证明fbp1改变的碳水化合物代谢和fbp1激活的P53可以通过激活AML原细胞的线粒体重编程来启动白血病死亡，支持基于fbp1的AML样癌症治疗的临床潜力。
Acute myeloid leukemia (AML)—the most frequent form of adult blood cancer—is characterized by heterogeneous mechanisms and disease progression. Developing an effective therapeutic strategy that targets metabolic homeostasis and energy production in immature leukemic cells (blasts) is essential for overcoming relapse and improving the prognosis of AML patients with different subtypes. With respect to metabolic regulation, fructose-1,6-bisphosphatase 1 (FBP1) is a gluconeogenic enzyme that is vital to carbohydrate metabolism, since gluconeogenesis is the central pathway for the production of important metabolites and energy necessary to maintain normal cellular activities. Beyond its catalytic activity, FBP1 inhibits aerobic glycolysis—known as the “Warburg effect”—in cancer cells. Importantly, while downregulation of FBP1 is associated with carcinogenesis in major human organs, restoration of FBP1 in cancer cells promotes apoptosis and prevents disease progression in solid tumors. Recently, our large-scale sequencing analyses revealed FBP1 as a novel inducible therapeutic target among 17,757 vitamin-D-responsive genes in MV4-11 or MOLM-14 blasts in vitro, both of which were derived from AML patients with FLT3 mutations. To investigate FBP1′s anti-leukemic function in this study, we generated a new AML cell line through lentiviral overexpression of an FBP1 transgene in vitro (named FBP1-MV4-11). Results showed that FBP1-MV4-11 blasts are more prone to apoptosis than MV4-11 blasts. Mechanistically, FBP1-MV4-11 blasts have significantly increased gene and protein expression of P53, as confirmed by the P53 promoter assay in vitro. However, enhanced cell death and reduced proliferation of FBP1-MV4-11 blasts could be reversed by supplementation with post-glycolytic metabolites in vitro. Additionally, FBP1-MV4-11 blasts were found to have impaired mitochondrial homeostasis through reduced cytochrome c oxidase subunit 2 (COX2 or MT-CO2) and upregulated PTEN-induced kinase (PINK1) expressions. In summary, this is the first in vitro evidence that FBP1-altered carbohydrate metabolism and FBP1-activated P53 can initiate leukemic death by activating mitochondrial reprogramming in AML blasts, supporting the clinical potential of FBP1-based therapies for AML-like cancers.
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