INHIBITION OF ISOPRENOID BIOSYNTHESIS INDUCES APOPTOSIS IN HUMAN PROMYELOCYTIC HL-60 CELLS

Protein isoprenylation is a posttranslational modification that facili tates membrane association and biological activity of a number of prot eins. Mevalonate is the precursor of cellular sterols as well as of is oprenoid lipids involved in protein modification. In this study we sho w that HL-60 cells treated with lovastatin, an inhibitor of mevalonate synthesis, exhibit alterations in growth and morphology, as well as c hanges in the subcellular distribution of isoprenylated proteins like nuclear lamin A and p21 Ras. Moreover, they are induced to die via apo ptosis, as evidenced by the appearance of a typical DNA fragmentation pattern. Lovastatin-induced DNA fragmentation can be specifically prev ented by mevalonate. The failure of several products of the mevalonate pathway, including cholesterol, to overcome lovastatin effect, points to the involvement of isoprenylated proteins in the mechanisms suppre ssing cell death. (C) 1994 Academic Press Inc.