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The Protein Kinase C Activators Phorbol Esters and Phosphatidylserine Inhibit Neutral Sphingomyelinase Activation, Ceramide Generation, and Apoptosis Triggered by Daunorubicin¹

Contrat Jeune Formation, Institut National de la Santé et de la Recherche Médicale 9503, Centre Claudius Régaud, Toulouse Cedex 31052 [V. M., G. L., A. B., J-P. J.]; Laboratoire de Biochimie Médicale, Institut National de la Santé et de la Recherche Médicale U466, Centre Hospitalier Universitaire Rangueil, Toulouse 31403 [T. L.]; and Service d'Hématologie Centre Hospitalier Universitaire Purpan, Toulouse 31059 [G. L.], France

To address the role of protein kinase C (PKC) in the regulation of ceramide production, we evaluated the impact of the PKC activators 12-O-tetradecanoylphorbol-13-acetate and phosphatidylserine on the apoptotic signaling pathway triggered by the chemotherapeutic drug daunorubicin. Treatment of U937 and HL-60 cells with 0.5–1 µM daunorubicin induced a greater than 30% activation of neutral sphingomyelinase activity within 4–10 min with concomitant sphingomyelin hydrolysis and ceramide generation. Activation of PKC by 12-O-tetradecanoylphorbol-13-acetate and phosphatidylserine inhibited daunorubicin-induced neutral sphingomyelinase activation, sphingomyelin hydrolysis, ceramide generation, and apoptosis. The apoptotic response could be restored by the addition of 25 µM cell-permeant C6-ceramide. In conclusion, PKC emerges as a potentially critical negative regulator of the anthracycline-activated sphingomyelin-ceramide apoptotic pathway.

¹ This study was supported in part by Grant 96003115 from La Fédération Nationale des Centres de Lutte Contre le Cancer (to J-P. J. and T. L.); by a grant from the Conseil Régional Midi-Pyrées (to T. L. and J-P. J.); by l'Association pour la Recherche sur le Cancer Grants 6749 (to G. L.), 3002 (to T. L.), and 2069 (to J-P. J.); and by a grant from La Ligue Nationale Contre le Cancer (to G. L.). V. M. is the recipient of an Institut National de la Santé et de la Recherche Médicale fellowship.

² To whom requests for reprints should be addressed, at CJF INSERM 9503, Centre Claudius Régaud, 20 rue du Pont St. Pierre, Toulouse Cedex 31052 France. E-mail: jaffrezou@regaud-tlse.fnclcc.fr.

Received 5/ 1/97. Accepted 10/ 3/97.

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