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Abolition of Mevinolin-induced Growth Inhibition in Human Fibroblasts following Transformation by Simian Virus 40¹

Department of Tumor Pathology, Karolinska Institutet, S-104 01 Stockholm, Sweden

The basal level of the gene expression and the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase was higher in SV40-transformed human fibroblasts (90-VA VI) than in normal ones (HDF). In both these cell types mevinolin (25 µM) caused an 85–90% depression of HMG CoA reductase activity and of the incorporation of [³H]acetate into sterols. In HDF this was coupled to an efficient block of cell growth, whereas the growth of 90-VA VI was only slightly reduced by mevinolin. In HDF, mevinolin (25 µM) also abolished essentially all dolichol synthesis, as measured by incorporation of [³H]acetate. In contrast, dolichol synthesis remained unaltered, or was increased, in mevinolin-treated 90-VA VI. We suggest that these different responses of dolichol synthesis may depend on different substrate affinities of the rate-limiting enzyme in the dolichol pathway. However, if 90-VA VI was treated with 25-hydroxycholesterol (25-OH), an alternative inhibitor of HMG CoA reductase, the cellular growth as well as dolichol synthesis was significantly decreased. Since the inhibitory effect of 25-OH on HMG CoA reductase activity did not exceed that of mevinolin, it seems that 25-OH, besides inhibiting HMG CoA reductase, inhibits steps distal to HMG CoA reductase. This notion was further supported by the finding that addition of mevalonate did not prevent the 25-OH-induced growth inhibition. However, if dolichol was added along with 25-OH, the block was partially prevented, indicating that a critical level of de novo synthesis of dolichol is essential for cellular growth.

¹ This work was supported by grants from the Swedish Cancer Society and the Stockholm Cancer Society and by the Research Funds of the Karolinska Institute.

² To whom requests for reprints should be addressed.

Received 7/19/88. Revised 5/23/89. Accepted 7/20/89.

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