Inhibition of the CXCR4/PLC Signaling Increases Dexamethasone-Induced Sensitivity by Activating the Mitochondrial Apoptotic Pathway in B-Cell Acute Lymphoblastic Leukemia DOI Open Access
Souleymane Abdoul‐Azize,

Jean‐Pierre Vannier,

Pascale Schneider

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3489 - 3489

Published: April 8, 2025

Understanding the mechanisms underlying glucocorticoid (GC) resistance in B-cell acute lymphoblastic leukemia (B-ALL) is essential to improve survival rates relapsed children. We previously showed that GCs paradoxically induced their own B-ALL through CXCR4/PLC signaling, and inhibition of this pathway significantly reverses GC cells improves GC-treated NSG mice vivo. Here, we sought determine whether enhancement sensitivity via axis associated with disruption mitochondrial pathway. Analysis our previous transcriptomic data revealed B-ALL, PLC inhibitor U73122 compromised multiple metabolic pathways related reprogramming, function, oxidative stress. Inhibition U73122, protein kinase C GF109203X, or CXCR4 AMD3100 potentiated dexamethasone (Dex)-induced membrane potential depolarization, reactive oxygen species production, cytochrome c release, caspase-3 activation, decreased O2 consumption cells. These observations were also confirmed after Dex treatment a Nalm-6 cell line transfected small interfering RNA. Moreover, co-treatment CXCR4, PKC, inhibitors increased levels pro-apoptotic BIM (BCL-2 interacting mediator death) and, consequently, promoted death process. Together, these findings suggest reduces efficacy by limiting apoptotic activity.

Language: Английский

Inhibition of the CXCR4/PLC Signaling Increases Dexamethasone-Induced Sensitivity by Activating the Mitochondrial Apoptotic Pathway in B-Cell Acute Lymphoblastic Leukemia DOI Open Access
Souleymane Abdoul‐Azize,

Jean‐Pierre Vannier,

Pascale Schneider

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3489 - 3489

Published: April 8, 2025

Understanding the mechanisms underlying glucocorticoid (GC) resistance in B-cell acute lymphoblastic leukemia (B-ALL) is essential to improve survival rates relapsed children. We previously showed that GCs paradoxically induced their own B-ALL through CXCR4/PLC signaling, and inhibition of this pathway significantly reverses GC cells improves GC-treated NSG mice vivo. Here, we sought determine whether enhancement sensitivity via axis associated with disruption mitochondrial pathway. Analysis our previous transcriptomic data revealed B-ALL, PLC inhibitor U73122 compromised multiple metabolic pathways related reprogramming, function, oxidative stress. Inhibition U73122, protein kinase C GF109203X, or CXCR4 AMD3100 potentiated dexamethasone (Dex)-induced membrane potential depolarization, reactive oxygen species production, cytochrome c release, caspase-3 activation, decreased O2 consumption cells. These observations were also confirmed after Dex treatment a Nalm-6 cell line transfected small interfering RNA. Moreover, co-treatment CXCR4, PKC, inhibitors increased levels pro-apoptotic BIM (BCL-2 interacting mediator death) and, consequently, promoted death process. Together, these findings suggest reduces efficacy by limiting apoptotic activity.

Language: Английский

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