FACTORS SECRETED BY TUMOR-TRANSFORMED FIBROBLASTS ELEVATE THE ACTIVITY OF HMG COA REDUCTASE - CORRELATION TO THE STIMULATIVE EFFECT ON DNA-SYNTHESIS

Abstract

Serum-free conditioned medium from virus-transformed murine and human fibroblasts (SV3T3 and 90VAVI) substantially increased the activity of HMG CoA reductase in normal cells (3T3 and HDF, respectively). The conditioned medium also stimulated normal cells to initiate DNA synthesis. Addition of mevinolin (an HMG CoA reductase inhibitor) depressed this increase in HMG CoA reductase activity with similar kinetics as it did in the transformed cells as well as in serum-stimulated normal cells. Whereas mevinolin efficiently blocked the proliferation of serum-stimulated normal fibroblasts, it only caused a partial growth inhibition in cells treated with conditioned medium. Likewise mevinolin failed to block the proliferation of the transformed cells. Taken together the present data suggest that virus-transformed fibroblasts produce and secrete factors stimulating mevalonate-dependent cell growth by two different mechanisms. Whereas some factors exert their stimulative effects on DNA synthesis by elevating the activity of HMG CoA reductase (secreted PDGF-like proteins may act in this manner), others may. mediate their growth stimulative effect by increasing the utilization of existing mevalonate in the production of growth regulatory metabolites.