HMGCoA reductase inhibition partially mediates tumor necrosis factor alpha-induced apoptosis in human U-937 and HL-60 cells.

We have examined the effects of tumor necrosis factor alpha (TNF alpha) and its second messenger, ceramide, on HMGCoA reductase, the rate-limiting enzyme in the mevalonate pathway. Treatment of human U-937 and HL-60 cells with TNF alpha or C2-ceramide inhibited both expression and activity of HMGCoA reductase in a time-dependent manner. Maturation of p21(ras) was also inhibited in a mevalonate-dependent fashion. The addition of mevalonate to both U-937 and HL-60 cells could also partially prevent TNF alpha and ceramide-induced apoptosis. These results support the hypothesis that the inhibition of HMGCoA reductase expression and the subsequent decrease in prenylation of proteins such as p21(ras) are part of the mechanism by which TNF alpha induces apoptosis in these cells.