MDR1, cholesterol esterification and cell growth: a comparative study in normal and multidrug-resistant KB cell Lines

The product of the MDR1 gene (P-gp) has been implicated in the transport of cholesterol from plasma membrane to endoplasmic reticulum for esterificati on. In previous studies on leukemia cell lines, we suggested that cholester ol esterification may regulate the rate of cell growth and that the MDR1 ge ne might be involved in this process by modulating intracellular cholestero l esters levels. To further investigate this matter, the rate of cell growt h, cholesterol metabolism, expression of the MDR1 gene, and P-gp activity w ere compared in KB cell lines displaying differences in expression and func tion of P-gp (drug-sensitive phenotype versus MDR phenotype). The rate of c ell growth correlated with cholesterol esterification in all KB cell lines, whereas the over-expression of MDR1 observed in the MDR cell lines was not always associated with an increased capacity of cells to esterify choleste rol. Two known inhibitors of P-gp activity, progesterone and verapamil, str ongly inhibited both cholesterol esterification and cell proliferation in a ll KB cell lines, but they affected intracellular accumulation of labeled v inblastine only in MDR cell lines. These results further support a role for cholesterol esters in the regulation of cell growth and suggest that the P -gp expressed in MDR KB cells is not involved in the general process leadin g to cholesterol esterification.