Interrelation of differentiation, proliferation and apoptosis in cancer cells.

Treatment of human leukemia HL-60 cells with ceramide, a breakdown product of sphingomyelin, induced both programmed cell death ("apoptosis"), and cellular differentiation. Apoptosis in response to ceramide occurred in a concentration-dependent manner. Apoptosis induced by ceramide in HL-60 cells requires the presence of c-jun protooncogene. However apoptosis is inhibited by curcumin, a specific inhibitor of c-jun/AP-1. Whereas curcumin restores ability of inhibited cells to grow, it does not affect ceramide-induced differentiation. These results indicate that ceramide controls cell differentiation and proliferation through apoptosis by activating the nuclear transcriptional factor AP-1. Further, AP-1 is apparently more closely related to apoptosis-inducing signal transduction pathway than to the pathway leading to cellular differentiation.