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Protein Kinase C Inhibition Induces Apoptosis and Ceramide Production through Activation of a Neutral Sphingomyelinase¹

Departments of Pathology [S. J. C., J. Q.] and Radiation and Cellular Oncology [E. N., R. R. W.], Division of Biological Sciences, University of Chicago and the Pritzker School of Medicine, Chicago, Illinois 60637

We report that WEHI-231 undergo apoptosis following exposure to the protein kinase C inhibitors chelerythrine chloride and calphostin C. Following the addition of chelerythrine or calphostin C to WEHI-231 cells, ceramide production increased over baselie levels with a concurrent decrease in sphingomyelin. More detailed examinations determined that the ceramide accumulation resulted from activation of neutral, but not acidic, sphingomyelinase. These results suggest an antagonistic relationship between protein kinase C activity and ceramide in the signaling events preceding apoptosis.

¹ This work was supported by NIH Grants GM07183, 5-R01-CA41068, 5-R01-CA42596, and PO1-CA-19266.

² To whom requests for reprints should be addressed, at Department of Radiation Oncology, University of Chicago Hospitals, 5841 South Maryland Avenue, MC 1089, Chicago, IL 60637. Phone: (312) 702-0817; Fax: (312) 702-1968; E-mail: rrw@rover.uchicago.edu.

Received 3/ 8/96. Accepted 4/30/96.

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