Melvalonates, Ras and Breast Cancer.
Annual rept. 1 Sep 97-31 Aug 98
TEXAS UNIV AT DALLAS SOUTHWESTERN MEDICAL CENTER
Pagination or Media Count:
This report documents progress on studies of the effects on breast cancer cell proliferation of reagents that inhibit mevalonate synthesis lovastatin or metabolism 6-fluoromevalonate Fmev, a mevalonate analogue. In our initial year we have established methods to quantitate cell proliferation and applied these in studies of the effects of the inhibitors. Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A HMU CoA reductase activity, induced apoptosis and suppressed the proliferation of breast cancer cell lines in a concentration- dependent and specific manner. Mevalonate restored cell growth and prevented apoptosis. In contrast, neither cholesterol nor precursors of farnesyl and geranylgeranyl pyrophosphate, was able to restore cell growth. These results implicate an essential requirement for mevalonate over and above its necessity for membrane synthesis cholesterol. Furthermore, they suggest that bypassing the block in post-translational prenylation of proteins is not sufficient to permit cellular proliferation. Fmev also inhibited breast cancer cell lines. In MCF-7 cells, the mechanism of suppression was the accumulation of a mevalonate-derived inhibitor. This effect was produced by elevated mevalonate synthesis, the result of poorly regulated HMG CoA redcutase activity. Ongoing studies are determining the effects of these inhibitors on intra-cellular Ras levels and its distribution.
- Medicine and Medical Research