Importance of mevalonate-derived products in the control of HMG-CoA reductase activity and growth of human lung adenocarcinoma cell line A549.

HMG-CoA reductase catalyzes the synthesis of mevalonate, a crucial intermediate in the biosynthesis of cholesterol and non-sterol isoprenoid compounds essential for cell growth. The HMG-CoA reductase activity of the A549 tumor cell line is higher than that of normal human fibroblasts. This deregulation in mevalonate needs was not due to an alteration in the activated state of the enzyme by short-term regulation. We show that the HMG-CoA reductase in A549 cell line was subject to a multivalent feedback control. A high fraction (40%) of the reductase activity was devoted to non-sterol products. In contrast, normal fibroblasts had only 15-20% of the reductase activity that generated non-sterol products. We also show that cholesterol and at least one of the non-sterol products are necessary for optimal cell growth of A549 cells. Our data strongly suggest that A549 cells produce more non-sterol substances which may be related to increased requirements of mevalonate for upregulated cell growth.