Multilevel regulation of low-density lipoprotein receptor and 3-hydroxy- 3-methylglutaryl coenzyme A reductase gene expression in normal and leukemic cells

Abstract

Abstract Altered cholesterol homeostasis has been noted in malignant cells, which led us to explore the regulation of cholesterol metabolism in normal and leukemic cells. The mean low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activities were fivefold and threefold higher in mononuclear blood cells from 33 patients with leukemia, compared with cells from 23 healthy subjects, whereas elevations in RNA levels were twofold and 40% only. The activities of the two proteins correlated in normal cells (r = .46), whereas an inverse correlation was found in leukemic cells (r = -.40). Relatively weak correlations were found between LDL receptor RNA levels and receptor activity in normal (r = .48) and leukemic cells (r = .49), and HMG-CoA reductase RNA levels correlated (r = .53) with reductase activity in leukemic cells only. The ratios of protein activities to RNA levels in cells were constant during consecutive blood samplings and similar in leukemic blood and bone marrow cells from the same individual. During cholesterol deprivation, protein activities increased more than RNA levels, and leukemic cells with high LDL receptor activity showed a partial resistance to the suppressing effect of sterols on LDL receptor gene expression. The results demonstrate that LDL receptor RNA levels alone can not explain variation in receptor activity, suggesting post-RNA regulation of LDL receptor expression, similar to what has been described for HMG-CoA reductase. Taken together, the present results suggest multilevel regulation of both proteins and demonstrate that each cell clone, normal or malignant, has a unique ratio of protein activity to RNA level. Leukemic cells, in contrast to normal cells, can meet increased cholesterol requirements by either elevated LDL receptor activity or increased cholesterol synthesis, which is of potential interest for diagnosis and specific treatment of leukemia.