Interaction Between Mevalonate Pathway and Retinoic Acid-Induced Differentiation

• Main Authors: Naima Gueddari-Pouzols, Patrick Duriez, Christine Chomienne, Aurélie Trussardi, Jean Claude Jardillier
• Format: Article
• Language: English
• Published: Hindawi Limited 2001-01-01
• Series: Journal of Biomedicine and Biotechnology
• Online Access: http://dx.doi.org/10.1155/S1110724301000183

All trans retinoic acid (ATRA) is a potent inducer of differentiation of HL-60 cell line. The pretreatment of the cells by compactin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl (HMG) CoA reductase, during 24 hours, enhances the ATRA-induced cell differentiation. At 50 nM, the percentage of cell differentiation is 34.9% ± 2 and 73% ± 2.96 in the control and compactin-treated cells, respectively. The removal of compactin boosts the level of HMG-CoA reductase and therefore the biosynthesis of sterol and nonsterol isoprenoid compounds. The participation of sterol and nonsterol pathway was then investigated. The supply of an excess of 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. A concomitant 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 differentiation mechanism.