Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells

Lovastatin is an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzym e A (HMG-CoA) reductase, the major regulatory enzyme of the mevalonate path way. We have previously reported that lovastatin induces a significant apop totic response in human acute myeloid leukemia (AML) cells. To identify the critical biochemical mechanism(s) essential for lovastatin-induced apoptos is, add-back experiments were conducted to determine which downstream produ ct(s) of the mevalonate pathway could suppress this apoptotic response. Apo ptosis induced by lovastatin was abrogated by mevalonate (MVA) and geranylg eranyl pyrophosphate (GGPP), and was partially inhibited by farnesyl pyroph osphate (FPP). Other products of the mevalonate pathway including cholester ol, squalene, lanosterol, desmosterol, dolichol, dolichol phosphate, ubiqui none, and isopentenyladenine did not affect lovastatin-induced apoptosis in AML cells. Our results suggest that inhibiting geranylgeranylation of targ et proteins is the predominant mechanism of lovastatin-induced apoptosis in AML cells. In support of this hypothesis, the geranylgeranyl transferase i nhibitor (GGTI-298) mimicked the effect of lovastatin, whereas the farnesyl transferase inhibitor (FTI-277) was much less effective at triggering apop tosis in AML cells. Inhibition of geranylgeranylation was monitored and ass ociated with the apoptotic response induced by lovastatin and GGTI-298 in t he AML cells. We conclude that blockage of the mevalonate pathway, particul arly inhibition of protein geranylgeranylation holds a critical role in the mechanism of lovastatin-induced apoptosis in AML cells.