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

Abstract

We have examined the effects of tumor necrosis factor α (TNFα) 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 TNFα or C2-ceramide inhibited both expression and activity of HMGCoA reductase in a time-dependent manner. Maturation of p21ras was also inhibited in a mevalonate-dependent fashion. The addition of mevalonate to both U-937 and HL-60 cells could also partially prevent TNFα 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 p21ras are part of the mechanism by which TNFα induces apoptosis in these cells.