Lovastatin-mediated G(1) arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase

In this paper we present the finding that lovastatin arrests cells by inhib iting the proteasome, which results in the accumulation of p21 and p27, lea ding to G(1) arrest. Lovastatin is an inhibitor of hydroxymethyl glutaryl ( HMG)-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Prev iously, we reported that lovastatin can be used to arrest cultured cells in the G(1) phase of the cell cycle, resulting in the stabilization of the cy clin-dependent kinase inhibitors (CKIs) p21 and p27, In this report we show that this stabilization of p21 and p27 may be the result of a previously u nknown function of the pro-drug, beta-lactone ring form of lovastatin to in hibit the proteasome degradation of these CKIs, The lovastatin mixture used in this study is 80% open-ring form and 20% pro-drug, beta-lactone form. W e show that while the lovastatin open-ring form and pravastatin (a lovastat in analogue, 100% open ring) inhibit the HMG-CoA reductase enzyme, lovastat in pro-drug inhibits the proteasome but does not inhibit HMG-CoA reductase. In addition, many of the properties of proteasome inhibition by the prodru g are the same as the specific proteasome inhibitor lactacystin, Lastly, me valonate (used to rescue cells from lovastatin arrest) unexpectedly abrogat es the lactacystin and lovastatin pro-drug inhibition of the proteasome. Me valonate increases the activity of the proteasome, which results in degrada tion of the CKIs, allowing lovastatin- and lactacystin-arrested cells to re sume cell division. The lovastatin-mediated inhibition of the proteasome su ggests a unique mechanism for the chemopreventative effects of this agent s een in human cancer.