Effect of virus-transformation and growth factor stimulation on isoprene biosynthesis in human fibroblasts: a correlation to cell growth.

Abstract

Serum depletion of exponentially growing normal human fibroblasts resulted in a moderate depression of the activity of HMG-CoA reductase which occurred 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 depletion on HMG-CoA reductase activity and cell growth. The growth inhibitory effect of serum depletion and mevinolin was correlated to a decreased biosynthesis of dolichols, in particular of dolichol-20. If PDGF was present in the serum-free medium a high rate of dolichol synthesis was maintained. This effect was mediated not only through an increased HMG-CoA reductase activity. PDGF also increased the incorporation of mevalonate into dolichols, once again into dolichol-20 in particular. In contrast to HDF, the growth of virus-transformed human fibroblasts was not decreased following serum depletion. This was correlated to a sustained activity of HMG-CoA reductase and a sustained dolichol-20 synthesis. In order to block growth and dolichol synthesis of the transformed fibroblasts a stronger inhibition of HMG-CoA reductase activity was required than in the normal cells. Conditioned medium isolated from the transformed cells was found to maintain a high growth rate and a high HMG-CoA reductase activity in serum-depleted HDF. In addition, the incorporation of mevalonate into dolichols was increased. The present data raise the possibility that PDGF or related factors, through autocrine loops, may contribute to the maintenance of a high dolichol synthesis in tumor cells.