The
statin family of drugs are well-established inhibitors of
3-hydroxy-3-methylglutaryl-CoA reductase and are used clinically in the control of
hypercholesterolemia. Recent evidence, from ourselves and others, shows that
statins can also trigger
tumor-specific apoptosis by blocking protein geranylgeranylation. We and others have proposed that
statins disrupt localization and function of geranylgeranylated
proteins responsible for activating signal transduction pathways essential for the growth and/or survival of transformed cells. To explore this further, we have investigated whether the
mitogen-activated protein kinase (MAPK) signaling cascades play a role in regulating
statin-induced apoptosis. Cells derived from
acute myelogenous leukemia (AML) are used as our model system. We show that p38 and c-Jun NH2-terminal
kinase/stress-activated
kinase MAPK pathways are not altered during
lovastatin-induced apoptosis. By contrast, exposure of primary and established AML cells to
statins results in significant disruption of basal
extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Addition of geranylgeranyl PPi reverses
statin-induced loss of ERK1/2 phosphorylation and apoptosis. By establishing and evaluating the inducible Raf-1:ER system in AML cells, we show that constitutive activation of the Raf/
MAPK kinase (MEK)/ERK pathway significantly represses but does not completely block
lovastatin-induced apoptosis. Our results strongly suggest
statins trigger apoptosis by regulating several signaling pathways, including the Raf/MEK/ERK pathway. Indeed, down-regulation of the Raf/MEK/ERK pathway potentiates
statin-induced apoptosis because exposure to the MEK1 inhibitor
PD98059 sensitizes AML cells to low, physiologically achievable concentrations of
lovastatin. Our study suggests that
lovastatin, alone or in combination with a MEK1 inhibitor, may represent a new and immediately available therapeutic approach to combat
tumors with activated ERK1/2, such as AML.