Inhibition of the CXCR4/PLC Signaling Increases Dexamethasone-Induced Sensitivity by Activating the Mitochondrial Apoptotic Pathway in B-Cell Acute Lymphoblastic Leukemia.
AI interpretation is pending for this paper.
Open original publication →What the AI sees
Not AI summarized yet.
Research significance
Pending deeper interpretation.
Source abstract
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.