Xia Z, Tan M M, Wong W W, Dimitroulakos J, Minden M D, Penn L Z
Department of Cellular and Molecular Biology, Ontario Cancer Institute, University Health Network, Toronto, Canada.
Leukemia. 2001 Sep;15(9):1398-407. doi: 10.1038/sj.leu.2402196.
Lovastatin is an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the major regulatory enzyme of the mevalonate pathway. We have previously reported that lovastatin induces a significant apoptotic response in human acute myeloid leukemia (AML) cells. To identify the critical biochemical mechanism(s) essential for lovastatin-induced apoptosis, add-back experiments were conducted to determine which downstream product(s) of the mevalonate pathway could suppress this apoptotic response. Apoptosis induced by lovastatin was abrogated by mevalonate (MVA) and geranylgeranyl pyrophosphate (GGPP), and was partially inhibited by farnesyl pyrophosphate (FPP). Other products of the mevalonate pathway including cholesterol, squalene, lanosterol, desmosterol, dolichol, dolichol phosphate, ubiquinone, and isopentenyladenine did not affect lovastatin-induced apoptosis in AML cells. Our results suggest that inhibiting geranylgeranylation of target proteins is the predominant mechanism of lovastatin-induced apoptosis in AML cells. In support of this hypothesis, the geranylgeranyl transferase inhibitor (GGTI-298) mimicked the effect of lovastatin, whereas the farnesyl transferase inhibitor (FTI-277) was much less effective at triggering apoptosis in AML cells. Inhibition of geranylgeranylation was monitored and associated with the apoptotic response induced by lovastatin and GGTI-298 in the AML cells. We conclude that blockage of the mevalonate pathway, particularly inhibition of protein geranylgeranylation holds a critical role in the mechanism of lovastatin-induced apoptosis in AML cells.
洛伐他汀是3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的抑制剂，该酶是甲羟戊酸途径的主要调节酶。我们之前报道过洛伐他汀可在人急性髓系白血病（AML）细胞中诱导显著的凋亡反应。为了确定洛伐他汀诱导凋亡所必需的关键生化机制，进行了回补实验以确定甲羟戊酸途径的哪些下游产物可以抑制这种凋亡反应。洛伐他汀诱导的凋亡被甲羟戊酸（MVA）和香叶基香叶基焦磷酸（GGPP）消除，并被法尼基焦磷酸（FPP）部分抑制。甲羟戊酸途径的其他产物，包括胆固醇、角鲨烯、羊毛甾醇、链甾醇、多萜醇、磷酸多萜醇、泛醌和异戊烯腺嘌呤，均不影响洛伐他汀诱导AML细胞凋亡。我们的结果表明，抑制靶蛋白的香叶基香叶基化是洛伐他汀诱导AML细胞凋亡的主要机制。为支持这一假设，香叶基香叶基转移酶抑制剂（GGTI-298）模拟了洛伐他汀的作用，而法尼基转移酶抑制剂（FTI-277）在触发AML细胞凋亡方面效果要差得多。监测了香叶基香叶基化的抑制情况，并将其与洛伐他汀和GGTI-298在AML细胞中诱导的凋亡反应相关联。我们得出结论，甲羟戊酸途径的阻断，尤其是对蛋白质香叶基香叶基化的抑制，在洛伐他汀诱导AML细胞凋亡的机制中起关键作用。
