Lovastatin inhibits G1/S transition of normal human B-lymphocytes independent of apoptosis

Lovastatin is a potent inhibitor of protein prenylation, and it has been re ported to have pleiotropic cellular effects. In the present study we have e lucidated the effects of lovastatin on cell cycle progression and apoptosis of normal human B-lymphocytes, When added to E-lymphocytes stimulated with anti-immunoglobulin (anti-mu) and SAG, lovastatin (20 mu M) inhibited the cells in the late G1 phase of the cell cycle. Thus, no early activation par ameters such as Ca2+ flux or MYC induction were affected by lovastatin, whe reas progression of cells into the second cell cycle as well as DNA synthes is was markedly reduced. We therefore examined the effects of lovastatin on components of the cell cycle machinery responsible for regulating the G1/S transition. We demonstrated that pRB phosphorylation, cdk2 activity needed for this phosphorylation, and the levels of cyclin A, D, and E were inhibi ted after 24 h of lovastatin treatment, while the levels of p27(Kip1) were elevated. There was no:effect on p21(Cip1), cyclin D2, cdk4, and cdk6. Thes e data are consistent with the cells being inhibited by lovastatin between 24 and 32 h into GI. Lovastatin added to stimulated B-cells in late GI stil l inhibited the DNA synthesis by 60%, but at this point only minor effects were noted on the cell cycle machinery. We therefore looked for induced apo ptosis as an explanation for reduced S-phase entry of the cells. However, d espite the ability to enhance the apoptosis of unstimulated B-cells from 48 to 61% as judged by the TUNEL method, lovastatin only marginally affected apoptosis when administered to stimulated B-cells. Thus, it appears that ac celerated apoptosis cannot account for the effect of lovastatin on cell cyc le progression. (C) 1999 Academic Press.