摘要
Understanding the mechanisms underlying glucocorticoid (GC) resistance in B-cell acute lymphoblastic leukemia (B-ALL) is essential to improve survival rates in relapsed children. We previously showed that GCs paradoxically induced their own resistance in B-ALL through CXCR4/PLC signaling, and that the inhibition of this pathway significantly reverses GC resistance in B-ALL cells and improves survival of GC-treated NSG mice in vivo. Here, we sought to determine whether the enhancement of GC sensitivity via inhibition of the CXCR4/PLC axis is associated with disruption of the mitochondrial pathway. Analysis of our previous transcriptomic data revealed that in B-ALL, the PLC inhibitor U73122 compromised multiple metabolic pathways related to metabolic reprogramming, mitochondrial function, and oxidative stress. Inhibition of PLC with U73122, protein kinase C with GF109203X, or CXCR4 with AMD3100 significantly potentiated dexamethasone (Dex)-induced mitochondrial membrane potential depolarization, reactive oxygen species production, cytochrome c release, caspase-3 activation, and decreased O2 consumption in B-ALL cells. These observations were also confirmed after Dex treatment in a B-ALL Nalm-6 cell line transfected with CXCR4 small interfering RNA. Moreover, co-treatment with Dex and CXCR4, PKC, or PLC inhibitors increased the levels of the pro-apoptotic protein BIM (BCL-2 interacting mediator of cell death) and, consequently, promoted the cell death process. Together, these findings suggest that the CXCR4/PLC axis reduces Dex efficacy by limiting mitochondrial apoptotic activity.
摘要译文
了解B细胞急性淋巴细胞白血病（B-All）中糖皮质激素（GC）耐药性的机制对于提高复发儿童的存活率至关重要。我们先前表明，GCS矛盾地通过CXCR4/PLC信号传导在B-ALL中诱导自己的耐药性，并且该途径的抑制作用显着逆转了B-ALL细胞中的GC耐药性，并提高了在体内GC处理的NSG小鼠的存活。在这里，我们试图确定通过抑制CXCR4/PLC轴增强GC灵敏度是否与线粒体途径的破坏有关。对我们先前的转录组数据的分析表明，在B-All中，PLC抑制剂U73122损害了与代谢重编程，线粒体功能和氧化应激有关的多种代谢途径。用U73122，具有GF109203X的蛋白激酶C或具有AMD3100的CXCR4抑制PLC，可显着增强的地塞米松（DEX）诱导的线粒体膜潜在去极化，caspase-3 Emplative and sold offectation，Caspase-3 Empantation和sold od sall od o2 of of of amd3100。在DEX处理后，在用CXCR4小型干扰RNA转染的B-ALL NALM-6细胞系中DEX处理后，这些观察结果也得到了证实。此外，与DEX和CXCR4，PKC或PLC抑制剂共同治疗增加了促凋亡蛋白BIM的水平（Bcl-2相互作用的细胞死亡介质），从而促进了细胞死亡过程。总之，这些发现表明CXCR4/PLC轴通过限制线粒体凋亡活性来降低DEX功效。
Souleymane Abdoul-Azize [1];Jean-Pierre Vannier [2];Pascale Schneider [3];. Inhibition of the CXCR4/PLC Signaling Increases Dexamethasone-Induced Sensitivity by Activating the Mitochondrial Apoptotic Pathway in B-Cell Acute Lymphoblastic Leukemia[J]. International Journal of Molecular Sciences, 2025,26(8): 3489