Overexpression of Protein Kinase C Confers Protection Against Antileukemic Drugs by Inhibiting the Redox-Dependent Sphingomyelinase Activation

ABSTRACT Induction of apoptosis by chemotherapeutic drugs involves the sphingomyelin-ceramide (SM-CER) pathway. This signaling is critically dependent on reactive oxygen species (ROS) generation and p53/p56 Lyn activation. In this study, we have investigated the influence of protein kinase C (PKC) overexpression on the SM-CER pathway in U937 human leukemia cell line. We show that PKC overexpression resulted in delayed apoptosis and significant resistance to both 1-␤-D-arabinofuranosylcytosine (ara-C) and daunorubicin (DNR), but there was no significant protection against cell-permeant C 6 -CER. Moreover, PKC overexpression abrogated drug-induced neutral sphingomyelinase stimulation and CER generation by inhibiting ROS production. We further investigated p53/p56 Lyn activation in PKC-overexpressing U937 cells treated with ara-C or DNR. We demonstrate that PKC inhibited p53/p56 Lyn phosphorylation and stimulation in drug-or H 2 O 2 -treated cells, suggesting that p53/p56 Lyn redox regulation is altered in PKC-overexpressing cells. Finally, we show that PKC-overexpressing U937 cells displayed accelerated H 2 O 2 detoxification. Altogether, our study provides evidence for the role of PKC in the negative regulation of drug-induced SM-CER pathway

Etude de l'activité cytotoxique des cellules de leucémie aigüe myéloïde

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Nouveaux mécanismes d'induction et de régulation de la voie de signalisation apoptotique CD95/FAS

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Impact des cytokines endo et exogènes sur l'activité in vitro des anticorps monoclonaux thérapeutiques dans la leucémie lymphoïde chronique

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

La leucémie lymphoïde chronique (de la physiopathologie à la prise en charge thérapeutique)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Impact des composantes cellulaires de la leucémie lymphoïde chronique de type B dans les rechutes post-thérapeutiques (de la Side population leucémique aux cellules immunitaires)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

CLL Cells from Ibrutinib-Induced Lymphocytosis of Relapsed/Refractory Chronic Lymphocytic Leukemia Patients Are Responsive to Obinutuzumab, but Not Rituximab, Ex Vivo

International audienc

Ibrutinib Exposure and B-Cell Depletion Induced By Anti-CD20 Monoclonal Antibodies Rituximab and Obinutuzumab: Is There a Rationale for Combination Studies?

International audienc

Modulation du métabolisme du céramide dans la réponse des cellules leucémiques aux rayonnements ionisants

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF