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De Toni-Costes F.,Institute National Des Science Et Of La Recherche Medicale | De Toni-Costes F.,University Paul Sabatier | Despeaux M.,Institute National Des Science Et Of La Recherche Medicale | Despeaux M.,University Paul Sabatier | And 11 more authors.
PLoS ONE | Year: 2010

Background: Cell survival mediated by integrin engagement has been implicated in cell adhesion-mediated drug resistance. We have recently demonstrated that the activation of glycogen synthase kinase 3 β (GSK3β) is a new pathway supporting the chemoresistance of leukemic cells adhered to fibronectin. Methodology and Principal Findings: We show here that in conditions of serum starvation, the fibronectin receptor α5β1 integrin, but not α4β1, induced activation of GSK3β through Ser-9 dephosphorylation in adherent U937 cells. The GSK3β dependent survival pathway occurred in adherent leukemic cells from patients but not in the HL-60 and KG1 cell lines. In adhesion, activated GSK3β was found in the cytosol/plasma membrane compartment and was co-immunoprecipitated with a5 integrin, the phosphatase PP2A and the scaffolding protein RACK1. PP2A and its regulatory subunit B′ regulated the Ser-9 phosphorylation of GSK3β. In adherent leukemic cells, α5β1 integrin but not α4β1 upregulated the resistance to TNF-α-induced apoptosis. Both extrinsic and intrinsic apoptotic pathways were under the control of α5β1 and GSK3β. Conclusions and Significance: Our data show that, upon serum starvation, α5β1 integrin engagement could regulate specific pro-survival functions through the activation of GSK3β. © 2010 De Toni-Costes et al. Source


Cuzin L.,University Hospital | Trabelsi S.,University Pierre and Marie Curie | Delobel P.,University Hospital | Delobel P.,Institute National Des Science Et Of La Recherche Medicale | And 10 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2012

Objective: To address the ability of a 24-week Maraviroc (MVC) intensification of a stable antiretroviral therapy (cART) to significantly increase the CD4 cell count slope. Methods: Patients were eligible if they had CD4 <350 cells/mm3, a CD4 slope <50 cells/mm3 per year, and sustained plasma HIV-RNA <50 copies/mL over the last 2 years, while receiving a stable cART. Patients harboring pure X4-using viruses by a phenotypic tropism assay were excluded. MVC was added to cART for 24 weeks, at the recommended dosage per drug-drug interactions. The primary endpoint was a significant positive difference in CD4 slopes (with MVC-pre-MVC, paired t test). Results: Sixty patients (55 men), with median age 51 years, baseline CD4 238 cells/mm3, and slope before intensification +14.1 cells/mm 3 per year were included. CD4 nadir was <50/mm3 in 47% of the population. The full set of patients (N = 57) completed week 24, and the on-treatment patients (N = 48) did not discontinue MVC. The median CD4 slope difference from baseline was +22.6 cells/mm3 per year (P = 0.08) in full set and +22.6 cells/mm3 per year (P = 0.04) in on-treatment. Slope evolution was not different according to baseline tropism, CD4 nadir, or ongoing cART regimen. No drug-related severe adverse events were recorded during intensification. MVC plasma concentrations were significantly different depending on drug-drug interaction with ongoing cART regimen and tended to be correlated with CD4 cells increase. Conclusion: In this study, MVC intensification of stable cART over 24 weeks was able to enhance CD4 cell slopes in patients with prior insufficient immune restoration despite long-term virological control. Copyright © 2012 by Lippincott Williams & Wilkins. Source

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