Overexpression of protein kinase Czeta confers protection against antileukemic drugs by inhibiting the redox-dependent sphingomyelinase activation.
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) zeta overexpression on the SM-CER pathway in U937 human leukemia cell line. We show that PKCzeta overexpression resulted in delayed apoptosis and significant resistance to both 1-beta-D-arabinofuranosylcytosine (ara-C) and daunorubicin (DNR), but there was no significant protection against cell-permeant C(6)-CER. Moreover, PKCzeta overexpression abrogated drug-induced neutral sphingomyelinase stimulation and CER generation by inhibiting ROS production. We further investigated p53/p56 Lyn activation in PKCzeta-overexpressing U937 cells treated with ara-C or DNR. We demonstrate that PKCzeta 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 PKCzeta-overexpressing cells. Finally, we show that PKCzeta-overexpressing U937 cells displayed accelerated H(2)O(2) detoxification. Altogether, our study provides evidence for the role of PKCzeta in the negative regulation of drug-induced SM-CER pathway.
Bezombes
Christine
C
Institut National de la Santé et de la Recherche Médicale U563, Institut Claudius Regaud, Toulouse, France. christinebezombes@yahoo.com
de Thonel
Aurélie
A
Apostolou
Andriana
A
Louat
Thierry
T
Jaffrézou
Jean-Pierre
JP
Laurent
Guy
G
Quillet-Mary
Anne
A
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors*; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology; D003561:Cytarabine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003630:Daunorubicin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008658:Inactivation, Metabolic; D010084:Oxidation-Reduction; D010766:Phosphorylation; D020011:Protective Agents / Q000494:pharmacology*; D011493:Protein Kinase C / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020298:U937 Cells; D019061:src-Family Kinases / Q000378:metabolism; D000099221:Protein Kinase C zeta
D000970:Antineoplastic Agents; D002518:Ceramides; D003561:Cytarabine; D003630:Daunorubicin; D006861:Hydrogen Peroxide; D020011:Protective Agents; D011493:Protein Kinase C; D017382:Reactive Oxygen Species; D013108:Sphingomyelin Phosphodiesterase; D016159:Tumor Suppressor Protein p53; D019061:src-Family Kinases; D000099221:Protein Kinase C zeta; C060902:lyn protein-tyrosine kinase