EFFECT OF VIRUS-TRANSFORMATION AND GROWTH-FACTOR STIMULATION ON ISOPRENE BIOSYNTHESIS IN HUMAN FIBROBLASTS - A CORRELATION TO CELL-GROWTH

Serum depletion of exponentially growing normal human fibroblasts resu lted in a moderate depression of the activity of HMG-CoA reductase whi ch occured simultaneously to the onset of growth arrest of the cells. Specific inhibition of HMG-CoA reductase using mevinolin also resulted in growth arrest. PDGF counteracted the suppressive effect of serum d epletion on HMG-CoA reductase activity and cell growth. The growth inh ibitory effect of serum depletion and mevinolin was correlated to a de creased biosynthesis of dolichols, in particular of dolichol-20. If PD GF was present in the serum-free medium a high rate of dolichol synthe sis was maintained. This effect was mediated not only through an incre ased HMG-CoA reductase activity. PDGF also increased the incorporation of mevalonate into dolichols, once again into dolichol-20 in particul ar. In contrast to HDF, the growth of virus-transformed human fibrobla sts was not decreased following serum depletion. This was correlated t o a sustained activity of HMG-CoA reductase and a sustained dolichol-2 0 synthesis. In order to block growth and dolichol synthesis of the tr ansformed fibroblasts a stronger inhibition of HMG-CoA reductase activ ity was required than in the normal cells. Conditioned medium isolated from the transformed cells was found to maintain a high growth rate a nd a high HMG-CoA reductase activity in serum-depleted HDF. In additio n, the incorporation of mevalonate into dolichols was increased. The p resent data raise the possibility that PDGF or related factors, throug h autocrine loops, may contribute to the maintenance of a high dolicho l synthesis in tumor cells.