{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T02:19:50Z","timestamp":1789957190526,"version":"4.0.1"},"reference-count":35,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T00:00:00Z","timestamp":1744070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ligue Contre le Cancer","award":["AK\/IP\/BC\/16094\/16792"],"award-info":[{"award-number":["AK\/IP\/BC\/16094\/16792"]}]},{"name":"Ligue Contre le Cancer","award":["IP\/BC-17040"],"award-info":[{"award-number":["IP\/BC-17040"]}]},{"name":"Comit\u00e9 D\u00e9partemental de la Ligue Contre le Cancer, Comit\u00e9 de Loire-Atlantique","award":["AK\/IP\/BC\/16094\/16792"],"award-info":[{"award-number":["AK\/IP\/BC\/16094\/16792"]}]},{"name":"Comit\u00e9 D\u00e9partemental de la Ligue Contre le Cancer, Comit\u00e9 de Loire-Atlantique","award":["IP\/BC-17040"],"award-info":[{"award-number":["IP\/BC-17040"]}]},{"name":"Association \u201cVie et Espoir\u201c","award":["AK\/IP\/BC\/16094\/16792"],"award-info":[{"award-number":["AK\/IP\/BC\/16094\/16792"]}]},{"name":"Association \u201cVie et Espoir\u201c","award":["IP\/BC-17040"],"award-info":[{"award-number":["IP\/BC-17040"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms26083489","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T03:32:53Z","timestamp":1744169573000},"page":"3489","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Inhibition of the CXCR4\/PLC Signaling Increases Dexamethasone-Induced Sensitivity by Activating the Mitochondrial Apoptotic Pathway in B-Cell Acute Lymphoblastic Leukemia"],"prefix":"10.3390","volume":"26","author":[{"given":"Souleymane","family":"Abdoul-Azize","sequence":"first","affiliation":[{"name":"University Rouen Normandie, Inserm, UMR 1234, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Vannier","sequence":"additional","affiliation":[{"name":"University Rouen Normandie, Inserm, UMR 1234, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Schneider","sequence":"additional","affiliation":[{"name":"University Rouen Normandie, Inserm, UMR 1234, 76000 Rouen, France"},{"name":"Department of Pediatric Immuno-Hemato-Oncology, University Hospital, 76000 Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Angot, L., Schneider, P., Vannier, J.-P., and Abdoul-Azize, S. (2023). Beyond Corticoresistance, A Paradoxical Corticosensitivity Induced by Corticosteroid Therapy in Pediatric Acute Lymphoblastic Leukemias. Cancers, 15.","DOI":"10.3390\/cancers15102812"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1080\/01635581.2025.2474263","article-title":"Poor Diet Quality Is Associated with Premature Senescence of the Immune System in Survivors of Childhood Acute Lymphoblastic Leukaemia","volume":"77","author":"Benmoussa","year":"2025","journal-title":"Nutr. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s11899-024-00735-w","article-title":"Glucocorticoid Therapy in Acute Lymphoblastic Leukemia: Navigating Short-Term and Long-Term Effects and Optimal Regimen Selection","volume":"19","author":"Pourhassan","year":"2024","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1111\/bjh.13852","article-title":"Towards an Understanding of the Biology and Targeted Treatment of Paediatric Relapsed Acute Lymphoblastic Leukaemia","volume":"172","author":"Irving","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"296","DOI":"10.2478\/raon-2018-0034","article-title":"Pharmacogenomic Markers of Glucocorticoid Response in the Initial Phase of Remission Induction Therapy in Childhood Acute Lymphoblastic Leukemia","volume":"52","author":"Gasic","year":"2018","journal-title":"Radiol. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Altieri, F., Buono, L., Lanzilli, M., Mirabelli, P., Cianflone, A., Beneduce, G., De Matteo, A., Parasole, R., Salvatore, M., and Smaldone, G. (2024). LINC00958 as New Diagnostic and Prognostic Biomarker of Childhood Acute Lymphoblastic Leukaemia of B Cells. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1388154"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1080\/14656566.2021.1931683","article-title":"Molecular-Based and Antibody-Based Targeted Pharmacological Approaches in Childhood Acute Lymphoblastic Leukemia","volume":"22","author":"Tardif","year":"2021","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.1038\/leu.2008.251","article-title":"Factors Influencing Survival after Relapse from Acute Lymphoblastic Leukemia: A Children\u2019s Oncology Group Study","volume":"22","author":"Nguyen","year":"2008","journal-title":"Leukemia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2374","DOI":"10.1038\/s41375-022-01685-z","article-title":"Epigenomic Profiling of Glucocorticoid Responses Identifies Cis-Regulatory Disruptions Impacting Steroid Resistance in Childhood Acute Lymphoblastic Leukemia","volume":"36","author":"Bergeron","year":"2022","journal-title":"Leukemia"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Tamai, M., Kasai, S., Akahane, K., Thu, T.N., Kagami, K., Komatsu, C., Abe, M., Watanabe, A., Goi, K., and Miyake, K. (2022). Glucocorticoid Receptor Gene Mutations Confer Glucocorticoid Resistance in B-Cell Precursor Acute Lymphoblastic Leukemia. J. Steroid Biochem. Mol. Biol., 218.","DOI":"10.1016\/j.jsbmb.2022.106068"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Li, X., Wu, T., Chen, W., Zhang, J., Jiang, Y., Deng, J., Long, W., Qin, X., and Zhou, Y. (2024). Andrographolide Acts with Dexamethasone to Inhibit the Growth of Acute Lymphoblastic Leukemia CEM-C1 Cells via the Regulation of the Autophagy-dependent PI3K\/AKT\/MTOR Signaling Pathway. Biomed. Rep., 20.","DOI":"10.3892\/br.2024.1731"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9697","DOI":"10.1038\/s41467-024-54096-2","article-title":"PU.1 Eviction at Lymphocyte-Specific Chromatin Domains Mediates Glucocorticoid Response in Acute Lymphoblastic Leukemia","volume":"15","author":"Beck","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1172\/JCI130189","article-title":"Glucocorticoids Paradoxically Facilitate Steroid Resistance in T Cell Acute Lymphoblastic Leukemias and Thymocytes","volume":"130","author":"Meyer","year":"2020","journal-title":"J. Clin. Invest."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1084\/jem.20050158","article-title":"IL-7 Receptor Signaling Is Necessary for Stage Transition in Adult B Cell Development through up-Regulation of EBF","volume":"201","author":"Kikuchi","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1038\/s41467-017-01388-5","article-title":"PLC\u03b3-Dependent MTOR Signalling Controls IL-7-Mediated Early B Cell Development","volume":"8","author":"Yu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3000","DOI":"10.1182\/blood-2017-02-766204","article-title":"Suppression of B-Cell Development Genes Is Key to Glucocorticoid Efficacy in Treatment of Acute Lymphoblastic Leukemia","volume":"129","author":"Kruth","year":"2017","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27339","DOI":"10.18632\/oncotarget.16039","article-title":"Improvement of Dexamethasone Sensitivity by Chelation of Intracellular Ca2+ in Pediatric Acute Lymphoblastic Leukemia Cells through the Prosurvival Kinase ERK1\/2 Deactivation","volume":"8","author":"Dubus","year":"2017","journal-title":"Oncotarget"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.ejphar.2016.05.014","article-title":"Pyr3, a TRPC3 Channel Blocker, Potentiates Dexamethasone Sensitivity and Apoptosis in Acute Lymphoblastic Leukemia Cells by Disturbing Ca2+ Signaling, Mitochondrial Membrane Potential Changes and Reactive Oxygen Species Production","volume":"784","author":"Buquet","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4557","DOI":"10.1038\/s41467-024-48818-9","article-title":"Glucocorticoids Paradoxically Promote Steroid Resistance in B Cell Acute Lymphoblastic Leukemia through CXCR4\/PLC Signaling","volume":"15","author":"Hami","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1476-4598-9-33","article-title":"Warburg Effect in Chemosensitivity: Targeting Lactate Dehydrogenase-A Re-Sensitizes Taxol-Resistant Cancer Cells to Taxol","volume":"9","author":"Zhou","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/cr.2017.155","article-title":"Mitochondrial Metabolism and Cancer","volume":"28","author":"Porporato","year":"2018","journal-title":"Cell Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6321","DOI":"10.1038\/s41388-021-02025-8","article-title":"Calcium-Dependent Signalling in B-Cell Lymphomas","volume":"40","author":"Berditchevski","year":"2021","journal-title":"Oncogene"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1182\/blood-2014-05-576470","article-title":"Opposing Regulation of BIM and BCL2 Controls Glucocorticoid-Induced Apoptosis of Pediatric Acute Lymphoblastic Leukemia Cells","volume":"125","author":"Jing","year":"2015","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Liu, X., Gu, J., Liu, S., Huang, J., Li, L., Wang, F., He, S., Mi, Z., Zhang, Y., and Wen, J. (2025). The Mitochondrial Protease ClpP Is a Promising Target for Multiple Myeloma Treatment. Biochem. Pharmacol., 236.","DOI":"10.1016\/j.bcp.2025.116855"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/s41419-025-07476-5","article-title":"SLC5A3 Depletion Promotes Apoptosis by Inducing Mitochondrial Dysfunction and Mitophagy in Gemcitabine-Resistant Pancreatic Cancer Cells","volume":"16","author":"Kim","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13046-024-03267-6","article-title":"ONC213: A Novel Strategy to Resensitize Resistant AML Cells to Venetoclax through Induction of Mitochondrial Stress","volume":"44","author":"Carter","year":"2025","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1111\/ejh.14006","article-title":"Augmenter of Liver Regeneration Promotes Drug Resistance of Acute Lymphoblastic Leukemia through the Alteration of Mitochondrial Functions and the Inhibition of the Mitochondrial Apoptosis Pathway","volume":"111","author":"Zhou","year":"2023","journal-title":"Eur. J. Haematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1038\/nm.4399","article-title":"Targeting Mitochondrial Oxidative Phosphorylation Eradicates Therapy-Resistant Chronic Myeloid Leukemia Stem Cells","volume":"23","author":"Kuntz","year":"2017","journal-title":"Nat. Med."},{"key":"ref_29","first-page":"2395","article-title":"Targeting Mitochondrial Respiration Selectively Sensitizes Pediatric Acute Lymphoblastic Leukemia Cell Lines and Patient Samples to Standard Chemotherapy","volume":"7","author":"Fu","year":"2017","journal-title":"Am. J. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Silic-Benussi, M., Sharova, E., Ciccarese, F., Cavallari, I., Raimondi, V., Urso, L., Corradin, A., Kotler, H., Scattolin, G., and Buldini, B. (2022). MTOR Inhibition Downregulates Glucose-6-Phosphate Dehydrogenase and Induces ROS-Dependent Death in T-Cell Acute Lymphoblastic Leukemia Cells. Redox Biol., 51.","DOI":"10.1016\/j.redox.2022.102268"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"112897","DOI":"10.1016\/j.intimp.2024.112897","article-title":"ROCK2 Increases Drug Resistance in Acute Myeloid Leukemia via Metabolic Reprogramming and MAPK\/PI3K\/AKT Signaling","volume":"140","author":"Yan","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1158\/2159-8290.CD-23-1145","article-title":"Targeting Acute Myeloid Leukemia Stem Cells through Perturbation of Mitochondrial Calcium","volume":"14","author":"Sheth","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_33","first-page":"130","article-title":"Modulation of Glucocorticoid Sensitivity in Acute Lymphoblastic Leukemia: Pyr3, a New Therapeutic Tool?","volume":"33","author":"Dubus","year":"2017","journal-title":"Med. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2657","DOI":"10.1182\/blood.2020008544","article-title":"Venetoclax and Dexamethasone Synergize with Inotuzumab Ozogamicin-Induced DNA Damage Signaling in B-Lineage ALL","volume":"137","author":"Kirchhoff","year":"2021","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4979","DOI":"10.1038\/s41388-018-0329-6","article-title":"Integration of Ca2+ Signaling Regulates the Breast Tumor Cell Response to Simvastatin and Doxorubicin","volume":"37","author":"Buquet","year":"2018","journal-title":"Oncogene"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3489\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:12:39Z","timestamp":1760029959000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3489"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,8]]},"references-count":35,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26083489"],"URL":"https:\/\/doi.org\/10.3390\/ijms26083489","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,8]]}}}