Interaction between mevalonate pathway and retinoic acid-induced differentiation

Abstract

All trans retinoic acid (ATRA) is a potent inducer of differentiation of HL-60 cell line. The pretreatment of thecells by compactin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl (HMG) CoA reductase, during 24 hours, enhances the ATRA-induced celldifferentiation. At 50 nM, the percentage of cell differentiation is 34.9% ± 2 and 73% ± 2.96 in the control and compactin-treatedcells, respectively. The removal of compactin boosts the level of HMG-CoA reductase and therefore the biosynthesis of sterol andnonsterol isoprenoid compounds. The participation of sterol and nonsterol pathway was then investigated. The supply of an excessof cholesterol (up to 80 μg/ml of LDL) leads to a significant decrease of cell differentiation by ATRA from 78% ±0.1 to 54% ±2.8. Aconcomitant decrease of cell growth (51% ± 6.4) was observed. The pretreatment of cells by the geranylgeranyltransferase inhibitor(GGTI-298) has no effect on the cell differentiation process. By contrast, the farnesyltransferase inhibitors (FTI-II and FTI-277)completely abolish theATRA-induced differentiation, thus confirming the involvement of farnesylated proteins in the differentiationmechanism. © 2001 Hindawi Publishing Corporation.